Porphycene compounds for photodynamic therapy

ABSTRACT

A porphycene having the structure ##STR1## wherein each R 1  is, independently, (a) --(CH 2 ) n  --X, where n=1-4, X is OR 2  and R 2  is C 1-6  alkyl, aralkyl or aryl; CN; OH; OSO 2  R 2  ; NH 2  ; NHR 2  ; NR 2   2  ; SH; SR 2  ; S(O) 1-2  R 2  ; COOH; CO 2  R 2  ; C(O)NH 2  ; C(O)NHR 2  ; C(O)NR 2   2  ; halogen; or CHO; 
     (b) --(CH 2 ) m  CH═CH 2  where m is 0-2; or 
     (c) --(CH 2 ) n  --O--G where G is a mono- or oligosaccharide; 
     (d) --(CH 2 ) 2n  --X, where X is an amino acid, oligopeptide covalently bonded by an ether-, ester- or amine-bond or --Y-- (CH 2 ) n  -porphycene 2  (porphycene 2  being a compound of the same structure and Y is a direct bond; --O--; or --CH═CH 2 ); or 
     (e) where one, two or three of the substituents R 1  are C 1-6  alkyl or aryl and the remaining substituents are as above under (a)-(d), and salts and metal complexes thereof. The porphycene compounds and pharmaceutical compositions containing the compounds are useful in photodynamic therapy treatment of tumors and psoriasis.

This is a division of application Ser. No. 07/875,314, U.S. Pat. No.5,262,401 filed on Apr. 29, 1992, which is a division of applicationSer. No. 07/723,394, U.S. Pat. No. 5,179,120 filed on Jun. 28, 1991.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to novel porphycene compounds and pharmaceuticalcompositions containing these compounds which are useful for therapeutictreatment.

2. Discussion of the Background

During the past few years there has developed a widespread recognitionthat modern, though sophisticated, cancer diagnosis and treatments haveserved neither to reduce overall the number of cases of reported cancersin the U.S.A. nor, save the notable cases, the death rate. This is adisheartening result for the billions of dollars invested in conqueringthe disease. Moreover, surgery, radiotherapy and chemotherapy are allassociated with major debilitating side effects such as trauma, severeimmunosuppression or toxicity which are not easily surmounted bypatients already compromised by ill-health.

Early work in the 1970's, followed by rapidly expanding studies in the1980's, has shown that photodynamic therapy (PDT) offers a viable, lesstoxic and generally less painful avenue to treatment of cancer. Not allcancers are candidates for PDT. However, neoplasms of hollow organs andskin, including multifocal carcinoma in situ, sometimes inoperable, andwith no good track record for treatment by established therapeuticprocedures, appear to be targets for PDT.

In photodynamic therapy, porphyrinoid dyes are administered to a patientand localize in neoplastic tissues (Lipson et al, J. ThoracicCardiovascular Surgery, 1961, 42:623-629). Irradiation of theporphyrinoid dye with light - at a wavelength which corresponds to anabsorption band of the dye results in destruction of the neoplastictissue. See also Kessel, D., "Methods in Porphyrin Photosensitization"Plenum Press, New York, 1985; Gomer, C. J., "Photodynamic Therapy",Petgammon Press, Oxford, 1987 and Doiron, D. R. and Gomer, C. J.,"Porphyrin Localization and Treatment of Tumors", Liss, New York, 1984.The use of a fiber optic laser light source is described in U.S. Pat.No. 4,957,481.

Dougherty et al (Cancer Res., 1978, 38:2628; Photochem. Photobiol, 1987,45:879) pioneered the field with infusion of photoactivatable dyes,followed by appropriate long wavelength radiation of the tumors (600+nm) to generate a lethal shortlived species of oxygen which destroyedthe neoplastic cells. Early experiments utilized a mixture termedhematoporphyrin derivative (HPD). See also Lipson et al, J.N.C.I., 1961,26:1; Dougherty et al, J.N.C.I., 1975, 55:115; Diamond et al, Lancet,1972(II), 1175; D. Dolphin, "The Porphyrins", vol I, Academic Press, NewYork, 1978; and D. Kessel, Photochem. PhotoBiol., 1984, 39:851. Thedeficiencies of HPD, especially prolonged phototoxicity caused byretained HPD components in human skin led to its displacement by apurified fraction termed dihematoporphyrin ether (DHE) which, althoughyielding improvements over HPD, nevertheless still suffered certainpractical limitations. Relatively weak absorption in the wavelengthrange above 600 nm, retention in dermal cells (potentially leading tophototoxicity), only modest or low selectivity for tumor cells versusother cell types in vital organs, the inability to use available,modern, inexpensive diode lasers, and uncertain chemical constitution ofthe mixtures are all known negative features of DHE and HPD. The greatmajority of the earlier PDT agents studied have been derived fromnatural sources (porphyrins, chlorins, purpurins, etc.) or from knownchemicals originating in the dyestuffs industry (e.g., cyanine dyes).For more recent PDT agents derived from natural sources see U.S. Pat.No. 4,961,920 and U.S. Pat. No. 4,861,876.

In animal and cell culture experiments one observes, following PDT,depending on the incubation time, damage to the vasculature, cellmembranes, mitochondria and specific enzymes. When absorbed in tumorcells, an increased selectivity can be obtained by injecting theporphyrinoid sensitizers enclosed in liposomes (Ricchelli and Jori,Photochem. Photobiol., 1986, 44:151). Porphyrinoid dyes can betransported in the blood with the aid of lipoproteins such aslow-density lipoprotein (Jori et al, Cancer Lett., 1984, 24:291).

PDT has been used to treat bladder, bronchial, bone marrow and skintumors (Dougherty, Photochem. Photobiol., 1987, 45:879, Sieber et al,Leukemia Res., 1987, 11:43) as well as severe psoriasis (Diezel et al,Dermatol. Monatsschr., 1980, 166:793; Emtenstam et al, Lancet, 1989 (I),1231). Treatment of viruses in transfused blood has also been reported(Matthews et al, Transfusion, 1988, 28:81; Sieber et al, Semin.Hematol., 1989, 26:35).

As the deficiencies of earlier PDT agents have become apparent, it alsobecomes possible to define activity parameters for improved chemicallypure photoactivatable dyes for PDT therapy, available by chemicalsynthesis. Moreover, the products of synthesis lend themselves morereadily to further chemical structural manipulation than do thenaturally occurring starting materials which can be expensive and bearchemically sensitive constituents. The synthesis of novel porphycenemacrocycles embracing four pyrrole rings has been described by Vogel andcoworkers. Alkylated porphycenes have also been prepared (R=Me, Et,n-Pr, n-octyl, phenyl) and the photochemical properties determined. Thesuitability of these compounds for PDT was noted and confirmed in animalstudies (Guardiano et al, Cancer Letters, 1989, 44, 1).

Synthetic efforts have focused on porphryinoid compounds which arehighly absorptive in the longer wavelength range of about 600-1200 nm,where the transparency of tissue is higher. Compounds such as purpurines(Morgan et al, J. Org. Chem., 1986, 51:1347; Morgan et al, Cancer Res.,1987, 47:496; Morgan et al, J. Med. Chem., 1989, 32:904; Hoober et al,Photochem. Photobiol., 1988, 48:579), naphthocyanin silicon complexes(Firey et al, J. Am. Chem. Soc., 1988, 110:7626), chlorins (Robert etal, J.N.C.I., 1988, 80:330; Kessel, Cancer Res., 1986, 46:2248),bacteriochlorins (Beams et al, Photochem. Photobiol., 1987, 46:639) andsubstituted phenylporphyrins (Kreimer-Birnbaum, Semin. Hematol., 1989,26:157) have been prepared and tested in vivo. Additional PDT agents aredescribed in EP 276,121.

Pyrrole-containing ring systems larger than porphycene have also beenprepared and evaluated as photosensitizers. Sessler et al have preparedand studied texaphyrin (J. Am. Chem. Soc., 1988, 110:5586) and Woodwardet al and Johnson et al have prepared and investigated the sapphyrinring system. Additionally, the platyrin system has been studied byLeGoff (Tetrahedron, Lett., 1978, 4225; J. Org. Chem., 1987, 710) andvinylogous porphyrins have been studied by Franck (Angew. Chem., 1986,98:1107; Angew. Chem. Int. Ed. Eng., 1986, 25:1100; Angew. Chem., 1988,100:1203; Angew. Chem. Int. Ed. Eng. , 1988, 27:1170).

A need continues to exist, therefore, for new compounds for use in PDTtherapy, which compounds are easily available, have low intrinsictoxicity, are efficient photosensitizers for singlet oxygen production,have selective uptake in rapidly proliferating cells, are rapidly or atleast moderately rapidly degraded and eliminated from the tissues afteradministration and which are available as chemically pure and stablecompounds easily subject to synthetic modification. The compound shouldpenetrate tissue quickly, especially if used for topical application.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide new andeffective compounds for use in photodynamic therapy whose properties andcharacteristics approach the ideal characteristics of PDT dyes listedabove.

This and other objects which will become apparent from the followingspecification have now been achieved with the compounds of the presentinvention. The present compounds have utility as PDT dyes for use incancer therapy and dermatological diseases, blood purification(elimination of viruses and bacteria, e.g., CMV, HIV), etc.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention and many of the attendantadvantages thereof will be readily obtained as the same becomes betterunderstood by reference to the following detailed description whenconsidered in connection with the accompanying drawing, wherein:

FIG. 1 illustrates a synthesis of the tetrakis(alkoxyalkyl)porphycenecompounds of the present invention, specificallytetrakis(methoxyethyl)porphycene.

FIG. 2 illustrates the preparation of mono-, bis-, tris- andtetrakis(bromoalkyl)porphycenatonickel compounds which, followingdemetallation, provide compounds of the present invention.

FIG. 3 illustrates the preparation of mono-, bis-, tris andtetrakis(hydroxyalkyl)porphycene compounds of the present invention.

FIG. 4 illustrates the preparation of porphycene carboxylic acidcompounds of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The porphycene compounds of the present invention have the structureshown below: ##STR2## where each R¹ in the 2, 7, 12 and 17-positions ofthe porphycene structure is, independently of one another, (a) the group--(CH₂)_(n) --X, where n=1-4, X is OR² and R² is C₁₋₆ alkyl, aralkyl oraryl; or X is CN; OH; OCOR² ; OSO₂ R² ; NH₂ ; NHR² ; NR₂ ² ; SH; SR² ;S(O)₁₋₂ R² ; COOH; C(O)NH₂, C(O)NHR², C(O)NR₂ ², CO₂ R² halogen or CHO;(b) the group --(CH₂)_(m) --CH═CH₂ where m=0-2 or (c) the group--(CH₂)_(n) --O--G where G is a mono- or oligosaccharide covalentlybonded to the porphycene or (d) the group --(CH₂)_(n) --X where X is anamino acid, oligopeptide covalently bonded by an ether-, ester- oramine-bond or Y(CH₂)_(n) -porphycene² (porphycene² being a compound ofthe same structure and Y is a direct bond; --O--; or --CH═CH--) or (e)where one, two or three of the substituents R¹ are C₁₋₆ alkyl or aryland the remaining substituents are as described above under (a)-(d),salts and metal complexes thereof. For all four substituents R¹ =alkyl,see U.S. Pat. No. 4,913,907.

Suitable aryl groups include C₆₋₂₀ carbocyclic aryl groups, optionallysubstituted with one or more C₁₋₆ alkyl groups. Examples include phenyl,naphthyl, indanyl etc. Suitable aralkyl groups are the aryl groupsdefined above bonded to a C₁₋₆ alkylene grop. Examples include benzyl,phenylethyl, phenylpropyl, phenylbutyl, etc.

Each amino acid may have either the D or L form. Preferred oligopeptideswill have 2-6 amino acid residues, more preferably 2-3 residues. It isconvenient to use the 20 naturally occurring amino acids.

The oligosaccharide covalently bonded to the porphycene may have 2-6,preferably 2-3 saccharide units. Both pentose and hexose saccharides maybe used, including, but not limited to, glucose, mannose, galactose andfructose.

Preferred compounds are those in which at least one R¹ is --(CH₂)_(n)--X where X is OR², OH, OCOR², OSO₂ R² or halogen (I, Br, Cl), andcompounds in which R¹ is --(CH₂)_(m) --CH═CH₂. Especially preferred arecompounds in which at least one R¹ is --(CH₂)₂ --X where X is OCH₃, OH,bromine and compounds in which R¹ is --(CH₂)_(n) --O--G, where G is apentose or hexose.

The compounds of the present invention may be prepared by couplingappropriately substituted dialdehydes to form the porphycene ringstructure as is shown below. ##STR3## Porphycenes with two differentsubstituents in the 2,7- and 12,17-positions are readily obtained bymixed coupling of two different dialdehydes as is shown below for thecase of 2,7-bis(methoxyethyl)-12,17-di -n-propylporphycene.

The coupling of the dialdehyde components may be accomplished with aMcMurry reaction utilizing low valency titanium in a non-reactivesolvent. See for example McMurry and Fleming, J. Am. Chem. Soc., 1974,96:4708; McMurry, Chem. Rev., 1989, 89:1513; Lenoir, Synthesis, 1989,883; Mukaiyama et al, Chem. Lett., 1973, 1041. Typically, reductivecoupling is carried out using a titanium amalgam prepared by reactingtitanium tetrachloride with an additional metal such as zinc, copper,aluminum and salts thereof. The reductive coupling reaction is carriedout in a non-reactive solvent such as a hydrocarbon or ether solvent.Typical solvents include alkanes having from 5-10 carbon atoms such aspentane, hexane, heptane, etc., as well as ether solvents such asdiethyl ether, crown ethers, glyme and tetrahydrofuran (THF). Ifdesired, the coupling reaction can be heated to facilitate the reaction,i.e., the reaction can be conducted under reflux conditions. Thedialdehyde components to gain the bis(alkoxyalkyl)-dialkylporphycenes,are on one hand those described below and, on the other hand, well knowndialdehydes, preferred in the present invention, such as5,5'-diformyl-4,4'-di-n-propyl-bipyrrole (e.g., E.Vogel et al; Angew.Chem. Int. Ed. Engl. 26 (1987)928).

Synthesis of compounds in which R¹ is --(CH₂)_(n) --X where X is OR²represent a convenient starting synthesis for the compounds of thepresent invention. With an appropriate cyano ether, it is possible tosynthesize the dialdehyde coupling components which ultimately providethe porphycene ring structure. Beginning with cyano ethers having thestructure R² O-(CH₂)_(n) --CN where R² is C₁₋₆ alkyl and n is 1-4, onecan systematically construct the dialdehyde coupling components requiredto prepare the porphycene derivatives in which R¹ is --(CH₂)_(n) --OR².FIG. 1 illustrates a synthesis of tetrakis(methoxyethyl)-porphycenestarting from the cyano ether in which R² is CH₃ and n=2. The remainingporphycene compounds in which R¹ is --(CH₂)_(n) --OR² can be synthesizedby an analogous synthetic procedure using the appropriate cyano ether.The cyano ethers may be purchased commercially or are available bycyano-dehalogenation displacement reactions on the correspondinghalo-ether (Friedrich and Wallenfels, in Rappoport, "The Chemistry ofthe Cyano Group", pages 77-86, InterScience, New York, 1970). Forexample, tetrakis(ethoxyethyl)-porphycene,tetrakis(propoxyethyl)porphycene, tetrakis(butoxyethyl)porphycene,tetrakis(pentoxyethyl)porphycene and tetrakis(hexyloxyethyl)porphycenecan be prepared from starting cyanoethers in which n=2 and R² isstraight chain or branched ethyl, propyl, butyl, pentyl and hexyl.Similarly, tetrakis(C₁₋₆ alkoxymethyl)porphycene, tetrakis(C₁₋₆alkoxypropyl)porphycene, tetrakis(C₁₋₆ alkoxybutyl)porphycene,tetrakis(C₁₋₆ alkoxypentyl)porphycene and tetrakis(C₁₋₆alkoxyhexyl)porphycene compounds can be prepared from the correspondingcyano ethers where R² is C₁₋₆ alkyl and n is 1, 3, 4, 5 or 6. Aparticularly preferred compound is tetrakis(methoxyethyl)porphycene. Thebromoester which is condensed with the cyano ether in the first stepshown in FIG. 1, is preferably a lower alkyl (C₁₋₆) bromo ester, morepreferably a methyl or ethyl ester.

Reaction of the tetrakis(alkoxyalkyl)porphycene as its nickel or zinccomplex, preferably the nickel complex, with about 0.7 moles of BBr₃/B(OH)₃ results in conversion of a single alkoxyalkyl group into thecorresponding bromoalkyl group. Reaction of about 1.2 moles of BBr₃/B(OH)₃ results in the corresponding bis(bromoalkyl)porphycenatonickelcomplex, and reaction with 2 moles of BBr₃ /B(OH)₃ gives thetris-product. The use of higher molar amounts of BBr₃ /B(OH)₃ providesthe tetrakis(bromoalkyl)porphycene compounds. The same products areobtained if solid boric acid is added to a solution of the substrateporphycene and boron tribromide is added subsequently.

The reaction is generally conducted at low temperatures, for exampleabout -40° to about -120° C., preferably about -78° C., and the reactionmixture then warmed to room temperature. The reaction is generallyconducted in an inert organic solvent which can be readily removed bydistillation or vacuum evaporation. Preferred solvents are halogenatedhydrocarbons and a particularly preferred solvent is dichloromethane.Purification of the desired brominated porphycenatonickel complex isaccomplished by conventional extraction and purification procedures.Preparation of the mono-, bis-, tris- andtetrakis(bromoalkyl)porphycenatonickel complex of a preferred embodimentof the present invention is shown in FIG. 2.

Metal complexes, preferably smaller metal complexes such as Ni⁺², Zn⁺²,etc of the porphycene compounds of the present invention can be easilyprepared by the addition of metal salts, e.g., metal acetates, to theporphycene compounds in acid medium, such as glacial acetic acid.Demetallation occurs when the metal complex is reacted with concentratedsulfuric acid at room temperature with stirring. Hydrogen ions displacethe metal atom during the demetallation reaction (Buchler, J. W. inSmith, K. M. (Ed): "Porphyrins and Metalloporphyrins", Elsevier,Amsterdam, 1975; Buchler, J. W. in Dolphin, D. (Ed), "The Porphyrins,"Vol. I, Academic Press, New York, 1978; Dorough et al, J. Am. Chem.Soc., 1951, 73:4315).

Reaction of the tetrakis(alkoxyalkyl)porphycene compounds with BBr₃ mayalso yield hydroxyalkyl porphycenes. By controlling the amount of borontribromide reagent, it is possible to optimize the production of 1, 2, 3or 4 hydroxyalkyl substituents (R¹ is --(CH₂)_(n) --OH), leaving theremaining alkoxyalkyl substituents intact. The synthesis of hydroxyalkylsubstituents on the porphycene is possible if boric acid is omitted andthe substrate is the uncomplexed porphycene.

The remaining compounds of the present invention are availablesynthetically by further reactions on any of the mono-, his-, tris- ortetrakis (bromoalkyl)- or (hydroxyalkyl) porphycene compounds. Olefinicgroups (R' is --(CH₂)_(m) --CH═CH₂), such as vinyl groups, can beintroduced into the porphycene compound by reaction of the appropriatebromoalkyl porphycene under dehydrohalogenation conditions. Loss of HBrresults in the synthesis of mono-, bis-, tris- andtetrakis(vinyl)porphycene compounds from the corresponding mono-, bis-,tris- and tetrakis(bromoethyl)porphycene compounds (n=2). Analogously, acarbon-carbon double bond can be introduced into substituent R¹ byeliminating HBr from a substituent having the formula --(CH₂)_(n) --Br,where n=3 or 4. The dehydrohalogenation can be conducted under anysuitable dehydrohalogenation conditions, generally through the additionof a base such as an alkoxide, amine or hydroxide base. For example,t-butoxide, diazobicycloundecene (DBU) or aqueous sodiumhydroxide/pyridine may be used to dehydrohalogenate the bromoalkylporphycene and thereby introduce a carbon-carbon double bond. Obviously,other dehydrohalogenation conditions not specifically disclosed aresuitable for the dehydrohalogenation reaction so long asdehydrohalogenation is effected. A particularly preferreddehydrohalogenating reagent is DBU.

Through dehydrohalogenation, porphycene compounds in which R¹ is--(CH₂)_(m) --CH═CH₂ where m is 0, 1 or 2 can be prepared. Thedehydrohalogenation reaction can be used to prepare porphycene compoundsin which 1, 2, 3 or 4 of the R¹ substituents contain a carbon-carbondouble bond by dehydrohalogenating the corresponding mono-, bis-, tris-or tetrakis(bromoalkyl)porphycene.

Additional porphycene compounds are available by displacing the bromineatom or better the methanesulfonate group, which is prepared in highyield from the hydroxy compound, in R¹ groups having the formula--(CH₂)_(n) --Br or --(CH₂)_(n) --OSO₂ CH₃ respectively. For example,nucleophilic displacement of a bromide ion by cyanide, chloride, iodide,ammonia, primary amines (NH₂ R²), secondary amines (HNR₂ ²), H₂ S andthiolate ions (--SR²) provides porphycene compounds where R¹ is--(CH₂)_(n) --X and X is I, Cl, CN, NH₂, NHR², NR₂ ², SH and SR².Conventional oxidation of the SR² group with known oxidizing agentsyields, the S(O)₁₋₂ R² groups (Oae, in Oae, "The Chemistry of Sulfur",Plenum, New York, 1977). These aliphatic nucleophilic substitutionreactions are well known in the art of organic synthesis (March,"Advanced Organic Chemistry, Reactions, Mechanisms, and Structure" 3rdEd John Wiley & Sows, New York, 1985 and references cited therein).

Hydrolysis of the cyano porphycene compounds (R¹ is --(CH₂)_(n) --CN)with alcoholic hydrogen chloride provides the corresponding carboxylicesters in which R¹ is --(CH₂)_(n) --COOR². These are readily convertedto the corresponding carboxylic acids, which can also be prepared byconventional hydrolysis methods but in low yield. Hydrolysis of theporphycene ester with alkali or alkaline earth metal hydroxide solutionsyields the corresponding alkali and alkaline earth metal carboxylatesalts by well known conventional hydrolysis reactions for example.

Carboxylic acid-containing porphycene compounds can further be convertedto the acid halide by the conventional addition of thionyl bromide,chloride, PBr₃ or PCl₃. The acid halide derivative is then readilyconverted to the corresponding amide by the addition of ammonia, aprimary amine or secondary amine to provide porphycene derivatives inwhich R¹ is --(CH₂)_(n) --C(O)NH₂, --(CH₂)_(n) --C(O)NHR², and--(CH₂)_(n) --C(O)NR₂ ². The acid halide derivative may also beconverted to the corresponding ester (R¹ is --(CH₂)_(n) --CO₂ R²) byreaction with an alcohol (HOR²). Esters may also be prepared byesterification of the carboxylic acid porphycene compounds using knownesterification reactions. Porphycene derivatives in which R¹ is--(CH₂)_(n) --CHO can be readily prepared by reducing the carboxylicacid to the aldehyde using known reagents such as (iso-Bu)₂ AlH or byoxidizing the alcohol (R¹ is --(CH₂)_(n-1) --CH₂ OH) using a weakoxidizing agent such as the chromium trioxide/pyridine, MnO₂ or othersuitable reagents (see March, loc. cit.).

To improve water solubility of the porphycene compounds, a saccharidemay be covalently attached to the porphycene via an ether linkage toprovide porphycene compounds in which R¹ is --(CH₂)_(n) --O--G, where Gis a monosaccharide. Preferred monosaccharides are pentose and hexosemonosaccharides such as glucose, galactose, mannose, xylose, fructose,etc. The monosaccharide derivatives can be prepared by known chemistry,for example by reacting a porphycene containing at least one R¹ grouphaving the formula --(CH₂)_(n) --OH with a OH-protected bromosaccharide,e.g., tetraacetyl bromoglucose. See the examples below and Fulling etal, Angew. Chem., 1989, 101:1550.

The monosaccharide-containing porphycene glycosides confer an increasedlevel of hydrophilicity to the porphycene compounds which facilitatesthe preparation of aqueous solutions for pharmaceutical use. Theglycosides have adequate solubility for preparation of aqueous,aqueous-alcoholic (preferably ethanolic) and aqueous dimethylsulfoxide(DMSO) solutions which may be directly topically applied for PDTtherapy. Topical application of these aqueous solutions is particularlyeffective for treating psoriatic lesions. To increase water solubilitythe porphycene compounds may also be covalently attached to an aminoacid or peptide by reaction of the substituent side chain, --(CH₂)_(n)--X (X=OH or halogen, for example) or --(CH₂)_(n) --CH═CH₂ with analcohol/phenol-, a carboxyl-, an amine or a thiol-group of the aminoacid or peptide.

The present invention includes porphycene metal complexes, for examplezinc, nickel, magnesium and tin complexes, of the porphycene compoundsdescribed above. The invention also includes pharmaceutically acceptableacid and base addition salts of the porphycene compounds which may beprepared by the known addition of acids such as HCl, HBr, H₂ SO₄, H₃PO₄, malic acid, tartaric acid, maleic acid, fumaric acid, etc. Baseaddition salts are prepared by the addition of alkali and alkaline earthmetal salts such as sodium, potassium, calcium and magnesium carbonates,bicarbonates, sulfates, phosphates, etc. as well as by addition ofammonia, amines, preferably primary, secondary and tertiary C₁₋₆ alkylamines, amino acids, etc. Any conventional acid or base addition saltwhich is pharmaceutically acceptable is considered to be within thescope of the present invention.

The porphycene compounds may also be covalently bonded to a stationaryphase, such as beads, plates, fibers, etc. by reaction of thesubstituent side chain, --(CH₂)_(n) --X (X═OH or halogen, for example)or --(CH₂)_(m) --CH═CH₂ with a reactive group in the stationary supportby addition or displacement reactions. When attached to a stationarysolid phase, the porphycene compounds may be used to purify anddecontaminate fluids passed over the solid phase. For example, blood foruse in transfusions or from a patient undergoing plasmaphoresisprocedures can be passed through a column containing resin beads havingbound thereto the porphycene compounds of the present invention.Irradiation of the porphycene dye bound to the solid support at theabsorption maximum wavelength for the particular porphycene dye resultsin the generation of singlet oxygen species which are lethal to viral,retroviral and bacterial contaminants in the blood or biological fluid.Addition of small amounts of the porphycene compounds into blood,followed by irradiation and subsequent transfusion into the patientundergoing therapy is also possible. The porphycene dyes are metabolizedin vivo and excreted from the patient.

The porphycene compounds of the present invention may be formulated astherapeutic formulations for administration to patients in need ofphotodynamic therapy.

THERAPEUTIC FORMULATIONS

Therapeutic compositions containing the compounds of the presentinvention include liposome or microvesicle preparations, dispersions,solutions for parenteral injection, etc. and including topicaldermatological preparations.

Parenteral Solutions

The photoactivatable porphycene dyes generally are used with additionalsolvents and adjuvants to prepare solutions suitable for intravenousinjection. A number of solvents and co-solvents that are miscible withwater and suitable surfactants can be used to achieve solutions forparenteral use. The most important solvents in this group are ethanol,polyethylene glycols of the liquid series and propylene glycol. A morecomprehensive listing includes acetone, dimethyl acetamide, dimethylformamide, dimethyl sulfoxide ethanol, glycerin, polyethylene glycol300, and 400, propylene glycol, sorbitol, polyoxyethylene sorbitan fattyacid esters such as laureate, palmitate, stearate, and oleate,polyoxyethylated vegetable oil, sorbitan monopalmitate, 2-pyrrolidone;n-methyl-2-pyrrolidine; n-ethyl-1-pyrrolidine; tetrahydrofurfurylalcohol, tween 80 and dimethyl isosorbide. Dimethyl isosorbide(ARLASOLVE® DMI, ICI Specialty Chemicals) has the advantage of beingboth water- and oil-soluble. Additionally, dimethyl isosorbide may bereadily gelled with a gelling agent to produce gel formulations with,for example, 4% KLUCEL® (Hercules).

Other additives may be necessary to enhance or maintain chemicalstability and physiological suitability- Examples are antioxidants,chelating agents, inert gases, buffers and isotonicifiers.

Examples of antioxidants and typical concentration ranges includeacetone sodium bisulfite (0.1-0.8%), ascorbic acid (0.05-1.0%),monothioglycerol (0.1-1.0%), potassium metabisulfite (0.05-0.1%), propylgallate (0.02%), sodium bisulfite (0.01-1.0%), sodium formaldehydesulfoxylate (0.03-0.1%), sodium metabisulfite (0.02-0.25%), sodiumsulfite (0.01-0.1%), sodium thioglycolate (0.05-0.1%).

Examples of chelating/complexing agents and typical concentration rangesinclude edetate sodium (0.005-0.1%), edetate calcium disodium(0.005%-0.01%), gentisic acid ethanolamide (1.0%-2.0%), niacinamide(1.0%-2.5%), sodium citrate (0.01%-2.5%), citric acid (0.001%-1.0%).

Examples of inert gases are nitrogen and carbon dioxide.

Buffers are used primarily to stabilize a solution against the chemicaldegradation that might occur if the pH changed appreciably. Buffersystems employed normally have as low a buffer capacity as feasible inorder to not disturb significantly the body buffer systems wheninjected. The buffer range and effect of the buffer on activity must beevaluated. Appropriate adjustment is useful to provide the optimumconditions for pH dependent partition into the target malignant tissuesor lesion area.

Examples of such buffer systems include the following acids: acetic,adipic, ascorbic, benzoic, citric, glycine, lactic, tartaric,hydrochloric, phosphoric, sulfuric, carbonic and bicarbonic; and theircorresponding salts such as: potassium, sodium, magnesium, calcium anddiethanolamine salts.

Osmoticity is of great importance and hypotonic solutions usually havetheir tonicity adjusted by the addition of salts such as sodiumchloride, potassium chloride, magnesium chloride and calcium chlorideand sugars such as dextrose, lactose, mannitol and sorbitol.

When the solution will be dispensed from multiple dose containers,antimicrobial agents in bacteriostatic or fungistatic concentrationsmust be added. Among the compounds and concentrations most frequentlyemployed are phenylmercuric acid (0.002-0.01%), thimerosal (0.01%),benzethonium chloride (0.01%), benzalkonium chloride (0.01%), phenol orcresol (0.5%), chlorbutanol (0.5%), benzyl alcohol (2.0%), methylp-hydroxybenzoate (0.18%), and propyl p-hydroxybenzoate (0.02%).

After the solution of the porphycene with its solvents and additives hasbeen compounded, the solution is generally filtered to removeparticulate matter above 2 μm in size and a further step eliminatingparticulate matter down to 0.2 μm can eliminate microorganisms andaccomplish cold sterilization. The solution is filled under asepticconditions. The final solution can be additionally sterilized in itsfinal container by thermal methods such as autoclaving or non-thermalmethods such as ionizing radiation. The process of freeze drying(lyophilization) can be employed to avoid adverse thermal and oxidativedecomposition and provide enhanced stability and improved solubility.

The following formula provides an example of the utilization of varioussolvents and additives such as have been heretofore mentioned in thecreation of a suitable parenteral solution of the porphycene. Theformula is by way of example only and is not limiting to this invention.Suitable combinations and variations are obvious to those skilled in theart.

    ______________________________________                                        Formula example for tetrakis(methoxyethyl)porphycene (TMEP)                                      Grams                                                      ______________________________________                                        TMEP                 0.1                                                      Tetrahydrofurfurylalcohol                                                                          40.0                                                     Polysorbate 20       1.0                                                      Sodium chloride      0.9                                                      Citric acid buffer   0.1                                                      water* enough to make 100 ml                                                  ______________________________________                                         *water may be water for injection, bacteriostatic water for injection or      sterile water for injection.                                             

Method of Preparation

1. Dissolve porphycene in tetrahydrofurfuryl alcohol and polysorbate 20,using heat and stirring as needed.

2. Dissolve sodium chloride and citrate buffer in water.*

3. Add the water solution slowly with stirring and heat as necessary tothe solution.

4. Sterile fill using aseptic conditions and use terminal sterilizationas needed.

This solution is suitable for a broad dosage range such as 0.1-10 mg/kgand preferably 0.2-5.0 mg/kg and may be infused as such or added tosuitable large volume parenteral solutions such as dextrose, saline,ringers solutions for slower intravenous administration. Suitablesolutions are described, for example, in REMINGTON'S PHARMACEUTICALSCIENCES, 15th Ed., Easton: Mack Publishing Co. incorporated herein byreference.

Topical Formulations

The porphycene compounds of the present invention may be formulated fortopical application in penetrating solvents or in the form of a lotion,cream, ointment or gel containing a sufficient amount of the porphycenecompound to be effective for PDT therapy.

Suitable penetrating solvents are solvents for the porphycene compoundwhich will enhance percutaneous penetration of the porphycene compound.Solvents which have this property include dimethyl sulfoxide, dimethylacetamide, dimethylformamide, 1-methyl-2-pyrrolidone,diisopropyladipate, diethyltoluamide and to a lesser extent propyleneglycol. Additional solvents include substituted azacycloalkan-2-oneshaving from 5 to 7 carbons in the cycloalkyl group such as1-dodecylazacycloheptan-2-one (AZONE) and other azacycloalkan-2-onessuch as described in U.S. Pat. No. 3,989,816 incorporated herein byreference.

Also included are N-bis-azocyclopentan-2-onyl alkanes described in U.S.Pat. No. 3,989,815 (hereby incorporated by reference), 1-substitutedazacyclopentan-2-ones described in U.S. Pat. No. 3,991,203 (herebyincorporated by reference) and water-soluble tertiary amine oxidesdescribed in U.S. Pat. No. 4,411,893 (hereby incorporated by reference).

The topical formulations contain a sufficient amount of the porphycenecompound to be effective in PDT therapy. Generally, concentrations inthe range of 0.001 to 5 wt. %, preferably from about 1 to 5 wt. %, maybe used. Typical lotion and cream formulations are shown below.

    ______________________________________                                        LOTION                                                                        Parts by Weight   Ingredient                                                  ______________________________________                                        5                 polyoxylene-40-sterate                                      3                 sorbitan monostearate                                       12                *mixture of lanolin,                                                          mineral oil and                                                               lanolin alcohol                                             6                 cetyl alcohol                                               20                soybean oil                                                 53.7              water                                                       0.2               methyl paraben                                              0.1               propyl paraben                                              ______________________________________                                         *AMERCOL BL (Amerchol Corp. Edison, N.J.)                                

    ______________________________________                                        CREAM                                                                         Parts by Weight   Ingredient                                                  ______________________________________                                        3                 polyoxylene-40-sterate                                      2.5               sorbitan monostearate                                       10                *mixture of lanolin,                                                          mineral oil and                                                               lanolin alcohol                                             10                cetyl alcohol                                               1                 soybean oil                                                 73.2              water                                                       0.2               methyl paraben                                              0.1               propyl paraben                                              ______________________________________                                         *AMERCOL BL (Amerchol Corp. Edison, N.J.)                                

Additional topical formulations which may be used in conjunction withthe porphycene compounds of the present invention are disclosed in U.S.Pat. No. 3,592,930 and U.S. Pat. No. 4,017,615 (hereby incorporated byreference).

Topical formulations may be prepared in gel form by combining theporphycene with a solvent such as diethyltoluamide (DEET) or diisopropyladipate (DIPA) and adding a gelling agent. A preferred gelling agent isfumed silica (CAB-O-SIL®, Cabot Corp., Tuscola, Ill.), and particularlygrade M-5. The gelling agent is generally used in amounts of about 5-12wt % to obtain a gel with the desired viscosity. Obviously, gelscontaining more or less gelling agent will have slightly higher or lowerviscosity. One skilled in the art can readily obtain the desired gelviscosity by adjusting the concentration of gelling agent. Additives,such as cosolvents and/or surfactants, frequently improve the gelproperties and may be added as desired. Suitable cosolvents/surfactantsinclude propylene glycol and glycerine. The additives may beincorporated into the gel by mechanically mixing the additives into amixture of solvent and gelling agent.

Liposome or Microvesicle Preparations

Liposomes and methods of preparing liposomes are known and are describedfor example in U.S. Pat. No. 4,452,747 and U.S. Pat. No. 4,448,765incorporated herein by reference. Liposomes are microvesicles whichencapsulate a liquid within lipid or polymeric membranes. The porphycenecompounds of the present invention may be incorporated into liposomemicrovesicles and used in this form for both topical and parenteralapplication. Topical and parenteral liposome preparations are known inthe art. Sonified unilamellar liposomes made from certain unsaturatedlipids are known stable carriers for some of the porphycenes of theinvention.

U.S. Pat. No. 4,837,028 discloses injectable liposome formulationshaving enhanced circulation time. The liposomes have a size of about0.08-0.5 microns, contain at least 50 mole % of a membrane rigidifyingcomponent such as sphingomyelin and further contain about 5-15 mole %ganglioside G_(M1). Liposome preparations for encapsulating sparinglysoluble pharmaceutical compounds are disclosed in U.S. Pat. No.4,721,612. The specification of these U.S. patents is incorporatedherein by reference.

After administration of a therapeutically effective amount of one ormore of the porphycene compounds in the pharmaceutical composition orpreparation, to a patient having a treatable condition such as a solidtumor (cancer) or psoriasis, for example, the patients affected bodyarea is exposed to a therapeutically sufficient amount of light havingan appropriate wavelength for absorption by the particular porphycenecompound used. Suitable wavelengths are generally from about 600 toabout 900 nm, preferably from about 600 to about 650 nm, more preferably620-650 nm. Irradiation of the accumulated porphycene generates singletoxygen which is thought to be the actual lethal species responsible fordestruction of the neoplastic cells.

Photodynamic therapy using the porphycene compounds of the presentinvention has a number of advantages. The porphycene compound itself isminimally toxic in the unexcited state. Each porphycene molecule can berepeatedly photoactivated and lead each time to cell-lethal events, thatis, the generation of singlet molecular oxygen. The half-life of singletmolecular oxygen is approximately four microseconds in water at roomtemperature. The target cell is therefore affected without theopportunity for migration of the lethal singlet molecular oxygen toneighboring healthy tissue cells. Preferably, the singlet oxygenmolecules rupture chemical bonds in the target cell wall or mitochondriaresulting in destruction of the target cell. Destruction of target celltissue commences promptly upon irradiation of the porphycene compounds.Indirect target cell death can also result from destruction of the tumorvascular system with concomitant restriction of oxygen supply.

Photodynamic therapy using the compounds of the present invention istherefore selective and minimally toxic to healthy tissue. Singletoxygen molecules produced which do not react rapidly decay to harmlessground state oxygen molecules.

A variety of phototherapy and irradiation methodologies are known tothose skilled in the art and can be used with the novel porphycenecompounds of the present invention. The time and duration of therapy andrepetition of the irradiation treatment can be selected by the therapist(physician or radiologist) according to known photodynamic therapycriteria. The dosage of the porphycene compound may be varied accordingto the size and location of the target tissues which are to be destroyedand the method of administration. Generally, the dosage will be in therange of 0.05-10 mg of porphycene compound per kilogram of body weight,more preferably in the range of 0.1-5.0 mg/kg.

Irradiation generally takes place not less than one hour nor more thanfour days after parenteral administration of the porphycene compound.Usually, phototherapy is begun approximately 3 hours to 48 hours afteradministration of the photodynamic therapy agent. With topicallyadministered dye, radiation may commence as soon as 10 minutes after dyeapplication for treatment of psoriasis, genital warts, bacterialinfections, etc. Exposure to non-therapeutic light sources should beavoided immediately following phototherapy to minimize light toxicity.Appropriate draping of the patient can be used to limit the areaaffected by phototherapy.

Light sources which are appropriate for use are well known in the artand may vary from white light sources with appropriate filters tolasers. As noted above, preferred wavelengths are from 600 to 950 nm,preferably from about 600 to about 800 nm. The total amount of lightwhich is applied to the affected area will vary with the method used andthe location of the tumor or topical lesion. Generally, the amount oflight is in the range of about 50 to 1000 J-cm² preferably in the rangeof 100 to 350 J-cm².

Having generally described this invention, a further understanding canbe obtained by reference to certain specific examples which are providedherein for purposes of illustration only and are not intended to belimiting unless otherwise specified. Procedures which are constructivelyreduced to practice herein are described in the present tense andprocedures which have been carried out in the laboratory are set forthin the past tense.

EXAMPLES Zinc/copper Pair

A solution of 20 g (0.1 mol) Cu(OAc)₂ --H₂ O in 400 mL of glacial aceticacid was treated rapidly with 196 g (3 mol) zinc powder with vigorousstirring. Within 15 seconds the solution discolored and was subsequentlystirred for 30 seconds. The solution was then filtered under inert gasand washed in succession twice with acetone, toluene, and absolute THF.The Zn/Cu pair thus produced can be used without drying.

5-Methoxy-3-oxopentanic acid alkylester (1) (see FIG. 1)

68 g (0.8 mol) of 3-methoxypropionitrile were dissolved in 1000 mL THFfreshly distilled over LiAlH₄ and treated with 150.3 g (2.2 mol) Zn/Cupair under inert gas. With moderate reflux 267.2 g (1.6 mol) of2-bromoacetic acid ethyl ester were added drop-by-drop to the vigorouslystirred suspension within 75 minutes. After the reaction had started,the heat was turned off and the slight reflux adjusted via the dropvelocity. To complete the reaction, the solution was stirred for 30minutes at the boiling temperature of THF. Then, 420 mL of 10% HCl wereadded drop-by-drop within 30 minutes at 15° C. and stirred for another30 minutes. The solution was filtered from the non-converted zinc andthe filtrate was extracted three times with 300 mL of CHCl₃ each. Theorganic phases were washed four times with water and once with 5% NaHCO₃solution and the solvent was removed following drying over MgSO₄ undervacuum. The obtained reddish liquid was distilled under oil pump vacuum.The fraction at 85° C./0.5 torr yielded 106.8 g (0.62 mol) of5-methoxy-3-oxopentanic acid ethyl ester as a colorless, fruity smellingoil with a refractive index n_(D) ²² =1.434. The yield was to 77.5%based on 3-methoxypropionitrile.

Elementary analysis: calculated: C 55.16% H 8.10% found: C 54.82% H7.92%

If 2-bromoacetic acid methyl ester is added as the α-bromoester, 97.2 g(0.61 mol) of 5-methoxy-3-oxopentanic acid methyl ester having a boilingpoint of 62°-63° C./0.12 torr are obtained with the same method. Therefractive index of the colorless oil, which was produced in a yield of76% based on 3-methylpropionitrile, is n_(D) ²¹ =1.435.

¹ H-NMR spectrum of (1a) (CDCl₃, 80 MHz), δ (ppm)=2.62 (triplet, 2H)MeOCH₂ CH₂ ; 3.16 (singlet, 3H) CH₃ OCH₂ ; 3.35 (singlet, 2H) COCH₂ CO;3.48 (triplet, 2H) MeOCH₂ ; 3.56 (singlet, 3H) CO₂ CH₃ ; signals at 4.9(singlet) and 2.3 ppm (triplet) through the enol form present in theequilibrium.

Mass spectrum of (1a), EI, 70 eV: m/z=160 (M+, 3%); 129 (M--OMe+, 12%);101 (M--CO₂ Me+, 40%); 100 (M--MeOCH₂ --CH₃ +, 33%); 87 (M--CH₂ CO₂ Me+,85%).

1H-NMR spectrum of (1b), CDCl₃, 80 MHz, δ (ppm)=1.06 (triplet, 3H) CH₂CH₃ ; 2.57 (triplet, 2H) MeOCH₂ CH₂ ; 3.10 (singlet, 3H) CH₃ OCH₂ ; 3.28(singlet, 2H) COCH₂ CO; 3.43 (triplet, 2H) MeOCH₂ ; 3.97 (quartet, 2H)CH₂ CH₃.

Mass spectrum of (1b), EI, 70 eV: m/z=174 (M+, 1%); 143 (M--OMe+, 12%);100 (M--MeOCH₂ --CH₂ CH₃ +, 40%); 87 (M--CH₂ CO₂ Et+, 85%).

IR spectrum of (1b), film: ν (cm⁻¹)=2987, 2941, 2903 (CH), 1743, 1724(C═O), 1118 (C--O, ether)

2.4-Bis(alkoxycarbonyl)-3-methoxyethyl-5-methylpyrroles (2)

While stirring and ice cooling, a cold saturated aqueous solution of 42g (0.6 mol) sodium nitrite was added so slowly drop-by-drop to asolution of 104.4 g (0.6 mol) methoxypentanoic acid ethyl ester in 450mL of glacial acetic acid, that no noticeable NO_(x) development wasdetected. The solution was stirred for two hours and treated with 83.2 g(0.64 mol) acetoacetic acid ethyl ester. Then while stirring vigorously,a mixture of 80 g (1.22 mol) of zinc powder and 100 g (1.22 mol) sodiumacetate was added in portions within 40 minutes. The inner temperatureranged from 80° to 85° C., a state that was reached by coolingoccasionally. Following completion of the addition, the solution wasstirred another 30 minutes and then filtered from the nonreacted zinc.The warm solution was poured into 4 L of water and left standingovernight to complete the precipitation. The raw product was filteredoff, washed with a little ice cold ether, dried over P₄ O₁₀ under vacuumfor one day, and recrystallized from ethanol/water. Thus, 113.2 g (0.4mol) 2,4-bis(ethoxycarbonyl)-3-methoxyethyl-5-methylpyrrole (2b) wasobtained as colorless needles with a melting point of 86° C. Yield: 65 %based on (1b). For further reaction of (2b) it was not necessary torecrystallize the raw product from ethanol/water.

Elementary analysis: calculated: C 59.16% H 7.47% N 4.94% found: C59.24% H 7.33% N 4.99%

The workup to isolate the corresponding pyrroldimethyl ester (2a) wasthe same as in the case of the application of 96 g (0.6 mol)5-methoxy-3-oxopentanoic acid methyl ester (1a) and 74.2 g (0.64 mol)acetoacetic acid methyl ester. However, the mother liquor of the firstcrystallization was extracted once with CHCl₃ and the solid obtainedfollowing neutralization and drying over MgSO₄ and evaporation of thesolvent was combined with the quantity of substance that precipitatedfirst. In this case recrystallization from methanol/water foresterification was avoided. The result was 96.4 g (0.38 mol) colorlessneedles of 2,4-bis (methoxycarbonyl) 3-methoxyethyl-5-methylpyrrole (2a), which melt at 118° C. Yield: 63%.

Elementary analysis: calculated: C: 56.46 H: 6.71 N: 5.49 found: C:56.42 H: 6.96 N: 5.45

¹ H-NMR spectrum of (2a), CDCl₃, 300 MHz, δ (ppm)=2.45 (singlet, 3H)α--CH₃ ; 3.33 (singlet, 3H) CH₃ OCH₂ ; 3.33 (triplet, 2H) MeOCH₂ CH₂ ;3.50 (triplet, 2H) MeOCH₂ ; 3.77 (singlet, 3H) β--CO₂ CH₃ ; 3.80(singlet, 3H) α--CO₂ CH₃ ; 9.98 (wide singlet) NH.

¹³ C-NMR spectrum of (2a), CDCl₃, 75.5 MHz, δ (ppm)=14.01 (α--CH₃);25.57 (MeOCH₂ CH₂); 50.66 (β--CO₂ CH₃); 51.36 (α--CO₂ CH₃); 58.1 H₃COCH₂); 72.78 (MeOCH₂ CH₂); 112.88 (C-4); 118.21 (C-2); 130.80 (C-3);139.86 (C-5) 161.94 (β--CO₂ CH₃); 165.44 (α--CO₂ CH₃).

Mass spectrum of (2a), EI, 70 eV: m/z=255 (M+, 12%); 223 (M--MeOH+,77%); 201 (M--MeOCH₂ +, 47%); 178 (M--MeOH--MeOCH₂ +, 100%).

IR spectrum of (2a), KBr pellet: ν (cm⁻¹)=3306, (NH); 2962, 2943, 2868(CH), 1711 (C=0).

UV/VIS spectrum of (2a) CH₂ Cl₂, λmax[nm] (ε)=227 (1.4×10⁴); 270(1.6×10⁴).

¹ H-NMR spectrum of (2b), CDCl₃, 80 MHz, δ (ppm)=1.33 (2 triplets, 6H)CH₂ CH₃ ; 2.48 (singlet, 3H) α--CH₃ ; 3.35 (singlet, 3H) CH₃ OCH₂ ; 3.45(A₂ B₂ system, 4H) MeOCH₂ CH₂ ; 4.27 (quartet, 2H) β--CO₂ CH₂ CH₃ ; 4.32(quartet, 2H) α--CO₂ CH₂ CH₃ ; 9.5 (wide singlet): NH.

IR spectrum of (2b) KBr pellet: ν (cm⁻¹) 3289, (NH); 2989, 2932, 2891(CH); 1703, 1663 (C=0); 1438 (CH).

Mass spectrum of (2b) EI, 70 eV: m/z=283 (M+, 13%); 251 (M--MeOCH₂ +,15%); 164 (M--MeOCH₂ --CH₃ --EtOH+, 18%).

UV/VIS spectrum of (2b), CH₂ Cl₂, λmax[nm] (ε)=226 (1.3×10⁴); 271(1.6×10⁴).

3,5-Bis(alkoxycarbonyl)-2-carboxy-4-methoxyethylpyrroles (3)

At one time 48 g (0.3 mol) of distilled bromine were added to a solutionof 85 g (0.3 mol) α-methylpyrroldiethyl ester in 280 mL glacial aceticacid and 55 mL of acetic anhydride at 0° C. Subsequently 128.5 g (1.05mol) freshly distilled sulfuryl chloride were added drop-by-drop at thistemperature in the dark over a period of two hours. Since the reactionsolution becomes viscous in the interim, the use of a KPG® stirrer isrecommended. The red solution obtained was then stirred at 0° C. for twohours. Then, 190 mL of water were added dropwise within 30 minutes, andthe inner temperature rose to 70° C. After another 30 minutes ofstirring, the mixture precipitated out by pouring in 2.5 L of water. Itwas left standing overnight and was filtered the next day. If the resultwas an oily raw product, it was decanted. At this stage the mixture wassuspended in 2 L of 70° C. warm water and treated in portions with solidNaHCO₃ until the generation of gas was no longer observed. It wasfiltered and slowly neutralized with semiconcentrated HCl while stirringvigorously. The mixture was left standing at 0° C. for eight hours inorder to complete the precipitation and the resulting fine crystallinesolid was filtered off. The pyrrolcarboxylic acid (3b) wasrecrystallized from ethanol/water and dried under vacuum for two days.47 g (0.15 mol) of colorless needles having a solid point of 136° C.were obtained. The yield of (3b) was 50%. For further reaction of (2b)it was not necessary to recrystallize the raw product fromethanol/water.

With the same method, 76.5 g (0.3 mol) methylpyrroldimethyl ester (2a)yield, following recrystallization from MeOH/water, 42.8 g (0.15 mol) of3,5-bis(methoxycarbonyl)-2-carboxy-4-methoxyethylpyrrole (3a). Thecolorless needles have a melting point of 142° C. The yield was 50%.

¹ H-NMR spectrum of (3a), CDCl₃, 300 MHz, δ (ppm)=3.36 (singlet, 3H) CH₃OCH₂ ; 3.45 (A₂ B₂ system, 4H) MeOCH₂ CH₂ ; 3.91 (singlet, 3H) β--CO₂CH₂ CH₃ ; 4.02 (singlet, 3H) α--CO₂ CH₃ ; 10.30 (wide singlet) NH.

IR spectrum of (3a), KBr pellet: ν (cm⁻¹) 3247 (NH); 2958, 2900 (CH),2616 (OH); 1722, 1632 (C═O); 1441 (CH).

Mass spectrum of (3a), EI, 70 eV: m/z=285 (M+, 28%); 270 (M--CH₃ +,11%); 253 (M--MeOH+, 85%); 222 (M--MeOH--MeO+, 100 %); 208 (M--MeOCH₂--MeOH+, 75%).

1H-NMR spectrum of (3b), CDCl₃, 80 MHz, δ (ppm)=1.38 (triplet, 3H)β--CO₂ CH₂ CH₃ ; 1.45 (triplet, 3H) α--CO₂ CH₂ CH₃ ; 3.33 (singlet, 3H)CH₃ OCH₂ ; 3.46 (A₂ B₂ system, 4H) MeOCH₂ CH₂ ; 4.40 (quartet, 2H)β--CO₂ CH₂ CH₃ ; 4.50 (quartet, 2H) α--CO₂ CH₂ CH₃ ; 10.25 (widesinglet) NH; 14.64 (wide singlet) CO₂ H.

IR spectrum of (3b), KBr pellet: ν (cm⁻¹) 3258, (NH); 2980, 2934, 2881(CH), 2568 (OH); 1737, 1693 (C═O); 1116 (C-0, ether).

Mass spectrum of (3b), EI, 70 eV: m/z=313 (M+, 34%); 281 (M--MeOH+,41%); 252 ([M--EtOH--CH₃ +, 28%); 222 (M--MeOCH₂ --EtOH+, 48%).

UV/VIS spectrum of (3b), CH₂ Cl₂, λmax[nm] (ε)=237 (2.7×10⁴); 257(9.2×10³); 288 (8.0×10³).

3,5-Bis(alkoxycarbonyl)-2-iodo-4-methoxyethylpyrroles (4)

While stirring, 47 g (0.15 mol) bis(ethoxycarbonyl) pyrrole carboxylicacid were suspended in 350 mL of water and treated in portions with 40.9g (0.48 mol) of sodium hydrogen carbonate at 75° C. At this stage asolution of 38.1 g (0.15 mol) I₂ and 49.8 g (0.3 mol) KI in 280 Ml ofwater were added dropwise to this clear solution within two hours. Thereaction solution foamed due to the resulting CO₂. The product (4b)began to precipitate after some time. Following completion of theaddition, the temperature was maintained for another 30 minutes whilestirring and then the still warm reaction solution was poured on 700 gof ice. The precipitate was filtered off, washed with water and ice coldpentane and recrystallized from ethanol so that colorless needles wereobtained. The 53.3 g (0.135 mol) of the title compound that wereobtained following drying under vacuum exhibit a melting point of 132°C. Yield: 90%.

Elementary analysis: calculated: C 39.51% H 4.59% N 3.54% found: C39.36% H 4.54% N 3.45%

When 42.8 g (0.15 mol) bis(methoxycarbonyl) pyrrolcarboxylic acid (3a)were used, 49.5 g (0.135 mol) iodopyrroledimethyl ester (4a) in 90%yield was obtained following recrystallization from methanol with thesame procedure. The melting point of the colorless needles was 114° C.

1H-NMR spectrum of (4a), CDCl₃, 80 MHz, δ (ppm)=3.35 (singlet, 3H) H₃COCH₂ ; 3.45 (A₂ B₂ system, 4H) MeOCH₂ CH₂ ; 3.84 (singlet, 3H) β-CO₂CH₃ ; 3.88 (singlet, 3H) α--CO₂ CH₃ ; 9.54 (wide singlet) NH.

Mass spectrum of (4a), EI, 70 eV: m/z=367 (M+, 28%); 355 (M--MeOH+,100%); 322 (M--MeOCH₂ +, 35%); 290 (M--MeOCH₂ --MeOH+, 59%).

IR spectrum of (4a), KBr pellet: ν (cm⁻¹)=3263 (NH); 2955, 2902 (CH),1676 (C═O); 1440 (CH); 1120 (C-0, ether).

UV/VIS spectrum of (4a) MeOH, CH₂ Cl₂, λmax[nm] (ε)=222 (2.0×10⁴); 266(1.8×10⁴). 1H-NMR spectrum of (4b), CDCl₃, 80 MHz, δ (ppm)=1.36(triplet, 3H) β--CO₂ CH₂ CH₃ ; 1.37 (triplet, 3H) α--CO₂ CH₂ CH₃ ; 3.34(singlet, 3H) CH₃ OCH₂ ; 3.46 (A₂ B₂ system, 4H) MeOCH₂ CH₂ ; 4.33(quartet, 2H) β--CO₂ CH₂ CH₃ ; 4.36 (quartet, 2H) α--CO₂ CH₂ CH₃ ; 9.5(wide singlet) NH.

Mass spectrum of (4b), EI, 70 eV: m/z=395 (M+, 30%); 363 (M--MeOH+,100%); 322 (M--CO₂ Et+, 31%); 276 (M--EtOH--CH₂ H₅ --MeOCH₂ +, 42%).

IR spectrum of (4b), KBr pellet: ν (cm⁻¹) 3140 (NH); 2989, 2830 (CH),1707 (C═O); 1105 (C-0, ether).

UV/VIS spectrum of (4b), CH₂ Cl₂, λmax[nm] (ε)=227 (1.4×10⁴); 267(1.8×10⁴).

3,3',5,5'-Tetrakis(alkoxycarbonyl)-4,4'-bis(methoxyethyl)2,2'-bipyrroles (5)

45 g (0.7 mol) copper bronze were added to a solution of 49.1 g (0.12mol) of iodopyrrolediethyl ester in 250 mL of absolute dimethylformamideand the mixture was stirred at room temperature for twenty hours. In sodoing, the suspension assumed a greenish-brown color. The raw productwas subsequently precipitated by slowly adding 1.2 L of water andfiltering off over Celite® together with the non-converted copper. Thefilter residue was extracted with 400 mL of hot chloroform. The extractwas washed briefly with 20% HNO₃, twice with water and once with 5%NaHCO₃ solution. After drying over MgSO₄ the solvent was evaporated andthe remaining solid was digested with 50 mL of cold hexane andsubsequently dried under oil pump vacuum. Following recrystallizationfrom ethanol, 39.9 g (74.4 mmol) of bipyrroltetraethyl ester (5b) wereobtained in the form of matted needles having a melting point of 150° C.Yield: 67%

Elementary analysis: calculated: C 58.20% H 6.76% N 5.22% found: C58.05% H 6.72% N 5.25%

Under analogous condition, 45.5 g (94.8 mmol) of bipyrrole (5a) wasrecovered from 44 g (0.12 mol) of the iodopyrroledimethyl ester (4a)following recrystallization from methanol. The melting point of thecolorless, matted needles was at 221° C. Yield: 79%.

¹ H-NMR spectrum of (5a), CDCl₃, 80 MHz, δ (ppm)=3.38 (singlet, 6H) H₃COCH₂ ; 3.50 (A₂ B₂ system, 8H) MeOCH₂ CH₂ ; 3.96 (singlet, 6H) β--CO₂CH₃ ; 3.98 (singlet, 6H) α--CO₂ CH₃ ; 13.95 (wide singlet) NH.

Mass spectrum of (5a), FAB, 75 eV: m/z=480 (M+, 76%); 449 (M--MeO+,40%); 417 (M--MeOH--MeO+, 24%); 403 (M--MeOCH₂ --MeOH+, 12%); 307(M--4MeOH--MeOCH₂ +, 33%).

IR spectrum, KBr pellet, ν (cm⁻¹)=2953, 2985 (CH), 1711 (C═O), 1451,1311.

UV/VIS spectrum of (5a), CHCl₃, λmax[nm] (ε)=250 (2.5×104); 288(1.5×10⁴); 346 (2.2×10⁴).

IR spectrum of (34b), KBr pellet: ν (cm⁻¹)=2988, 2893 (CH), 1716 (C═O),1479, 1383 (CH); 1117 (C-0, ether).

¹ H-NMR spectrum of (5b), CDCl₃, 80 MHz, δ (ppm)=1.41 (triplet, 3H)β--CO₂ CH₂ CH₃ : 1.42 (triplet, 3H) α--CO₂ CH₂ CH₃ ; 3.34 (singlet, 6H)H₃ COCH₂ ; 3.49 (A₂ B₂ system, 8H) MeOCH₂ CH₂ ; 4.39 (quartet, 4H)β--CO₂ CH₂ CH₃ ; 4.43 (quartet, 4H) α--CO₂ CH₂ CH₃ ; 14.10 (widesinglet) NH.

Mass spectrum of (5b) EI, 75 eV: m/z=536 (M+, 100%); 504 (M--MeOH+, 3%);490 (M--MeO--CH+, 11%); 445 (M--MeOCH₂ --EtOH+, 26%) .

UV/VIS spectrum of (5b), CH₂ Cl₂, λmax[nm] (ε)=228 (1.9×10⁴); 249(2.6×10⁴); 289 (1.5×10⁴); 347 (2.3×10⁴).

3,3',5,5'-Tetracarboxy-4,4'-bis(methoxyethyl)-2,2'-bipyrrole (6)

A solution of 26.8 g (50 mmol) of bipyrrole tetraethyl ester (5b) or 24g (50 mmol) of tetramethyl ester (5a) in 1350 mL of methanol weretreated with a solution of 30 g (0.75 mol) NaOH in 540 mL of water andheated with reflux for 40 hours. Following distillation of methanol, themixture was diluted with water to 4 L and slowly neutralized withdiluted hydrochloric acid while stirring. The mixture was stirred at theneutral point for fifteen minutes at room temperature and thenprecipitated at pH 2 with the further addition of acid. The mixture wasleft standing at 0° C. for six hours and the precipitate was filtered,washed with water and dried for five days over P₄ O₁₀ under vacuum. 1.5g (46 mmol) of a colorless to slightly greenish powder was obtainedthat, following recrystallization from DMSO/water yielded amicrocrystalline, colorless substance, which decomposed at 248° C.

Elementary analysis: calculated: C 50.95% H 4.75% N 6.60% found: C50.94% H 4.87% N 6.47%

¹ H-NMR spectrum of (6), DMSO-d₆, 300 MHz, δ (ppm)=3.23 (singlet, 6H) H₃COCH₂ ; 3.40 (A₂ B₂ system, 8H) MeOCH₂ CH₂ ; 12.70 (very wide singlet)CO₂ H; 13.15 (wide singlet) NH.

¹³ C-NMR spectrum of (6), DMSO-d₆, 75.5 MHz, δ (ppm) =25.27 (MeOCH₂CH₂); 57.61 (H₃ COCH₂); 72.50 (MeOCH₂ CH₂); 114.83, 120.52, 129.61,132.68 (C-2, 3, 4, 5): 161.78, 167.22 (CO₂ H).

UV/VIS spectrum of (6), DMSO, λmax[nm] (ε)=258 (1.5×10⁴); 277 (1.5×10⁴);343 (1.3×10⁴).

Mass spectrum of (6), EI, 70 eV: m/z=292 (M--3CO₂ +, 10%); 248 (M--4CO₂+, 36%); 203 (M--4CO₂ MeOCH₂ +, 26%); 171 (M--4CO₂ --MeOCH₂ --MeOH+,100%).

IR spectrum of (6), KBr pellet, ν (cm⁻¹)= 2922 (CH), 1633 (C═O), 1554,1187, 756.

4,4'-Bis(methoxyethyl)-2,2'-bipyrrole (7)

8.5 g (20 mmol) of bipyrrole tetracarboxylic acid (6) weredecarboxylated in a sublimator at 230° C. (bath temperature)/0.1-0.2torr. The product (7) separated as a colorless, amorphous or pale greencrystalline solid. The bipyrrole (7) decomposed slowly above 75° C. andmelts when rapidly heated at 98° C. Weighing yielded 4.7 g (18.8 mmol)of the title compound in a 94% yield.

The bipyrrole was sensitive to acid and oxygen and was stored underprotective gas at low temperature.

¹ H-NMR spectrum of (7), acetone-d₆, 300 MHz, δ (ppm)=2.64 (triplet, 4H)MeOCH₂ CH₂ ; 3.27 (singlet, 6H) H₃ COCH₂ ; 3.46 (triplet, 4H) MeOCH₂ CH₂; 6.11 (multiplet, 2H) H at C-3; 6.2 (multiplet, 2H) H at C-5; 9.79(wide singlet) NH.

Mass spectrum of (7), EI, 70 eV: m/z=248 (M+, 82%); 203 (M--MeOCH₂ +,28%); 171 (M--MeOCH₂ --MeOH+, 100%); 157 (M--MeOCH₂ --MeOCH₃ +, 33%).

IR spectrum (7), KBr pellet, ν (cm⁻¹)=3284 (NH); 3123, 3089, 2949, 2852(CH) 1568, 1185, 1082, 946, 802.

UV/VIS spectrum of (7), CH₃ CN, λmax[nm] (ε)=343 (8.0×10²); 284(1.8×10⁴).

5,5'-Diformyl-4,4'-bis(methoxyethyl)-2,2-bipyrrole (8)

6.14 g (40 mmol) of distilled phosphoryl chloride was added dropwise toa solution of 2.48 g (10 mmol) bipyrrole (7) in 50 mL of absolutedimethylformamide under protective gas at 0° C. within 30 minutes. Themixture was heated to 60° C. for one hour and subsequently poured into asolution of 60 g sodium acetate in 480 mL of water. The mixture wasstirred for one hour at 85° C., wherein the dialdehyde (8) precipitatedout in yellow flakes. The solution was cooled to 0° C., the precipitatefiltered off and washed with cold water. After drying over P₄ O₁₀ undervacuum, 2.58 g (8.5 mmol) of the title compound which was recrystallizedfrom tetrahydrofuran, were obtained. The title compound decomposes at186° C. without melting. The yield was 85%.

Elementary analysis: calculated: C: 63.14 H: 6.62 N: 9.21 found: C:63.07 H: 6.54 N: 9.15

¹ H-NMR spectrum of (8), CDCl₃, 300 MHz, 5 (ppm)=3.03 (triplet, 4H)MeOCH₂ CH₂ ; 3.37 (singlet, 6H) H₃ COCH₂ ; 3.62 (triplet, 4H) MeOCH₂ CH₂; 6.54 (doublet, 2H) H at C-3; 9.7 (singlet, 2H) CHO; 12.27 (widesinglet) NH.

¹³ C-NMR spectrum of (8), 75.5 MHz, δ (ppm)=26.03 (MeOCH₂ CH₂); 58.74(H₃ COCH₂); 72.91 (MeOCH₂ CH₂); 111.79, 130.60, 131.57, 136.10 (C-2, 3,4, 5), 177.71 (C-5¹).

Mass spectrum of (8), EI, 75 eV: m/z=304 (M+, 100%); 272 (M--MeOH+, 9%);227 (M--MeOCH₂ --MeOH+, 19%); 199 (M--MeOCH₂ --MeOH--CO+, 19%) .

IR spectrum of (8), KBr pellet: ν (cm⁻¹)=3266 (NH); 2925, 2868 (CH),1648 (C═O), 1116 (C-0, ether) 1607, 809.

UV/VIS spectrum of (8), CH₂ Cl₂ λmax[nm] (ε)=235 (9.6×10³); 271(1.5×10⁴); 381 (3.6×10⁴).

2,7,12,17-Tetrakis(methoxyethyl)porphycene (9)

Under protective gas over 10 minutes, 16.5 ml (0.15 mol) TiCl₄ wereadded dropwise to a suspension of 19.6 g (0.3 mol) zinc powder and 1.95g (9.5 mmol) CuCl in 800 mL of THF freshly distilled over LiAlH₄.Subsequently the mixture was heated with reflux for three hours. At thisstage a solution of 1.83 g (6 mmol) dialdehyde (8) in 600 mL of absoluteTHF was added dropwise within 20 minutes to the black McMurry reagentthus prepared while stirring vigorously. The reaction can be followed bymeans of thin layer chromatography (silica gel/CH₂ Cl₂). The reactionwas stirred for ten minutes at the boiling temperature of thetetrahydrofuran and then cooled to 0° C. At this temperature 300 ml of6% NH₃ solution were added dropwise over one hour. The reaction mixturewas treated with 600 mL of dichloromethane and filtered off over Celite®after fifteen minutes of stirring. The residue was extracted withanother 200 mL of CH₂ Cl₂ and the combined organic phases were washedthree times with 300 mL of water. Following drying over MgSO₄, thesolvent was evaporated under vacuum and the residue was chromatographedwith CH₂ Cl₂ on Al₂ O₃ (Brockmann, II-III activity, column 5×10 cm). Thefirst blue, red fluorescing fraction was collected and rechromatographedwith CH₂ Cl₂ /ethylacetate/methanol (100:20:1) on silica gel (column4×40 cm) in order to separate any possibly existing small quantities ofdegraded porphycenes as a small blue fraction, which was eluted prior tothe title compound. Following evaporation of the solvent andcrystallization from CH₂ Cl₂ /MeOH, (9) was obtained in the form oflong, violet, metallically glistening needles having a melting point of172° C. A 25% yield of 406 mg (0.75 mmol) of the porphycene tetraether(9) was obtained.

Elementary analysis: calculated C 70.83% H 7.06% N 10.32% found C 70.71%H 6.93% N 10.40%

¹ H-NMR spectrum of (9), CDCl₃, 300 MHz, δ (ppm)=3.11 (wide singlet) NH;3.60 (singlet, 12H); 4.31 (singlet, 16H) MeOCH₂ CH₂ ; 9.34 (singlet, 4H)H at C-3, 6, 13, 16; 9.71 (singlet, 4H) H at C-9, 10, 19, 20.

¹³ C-NMR spectrum of (9), CDCl₃, 75.5 MHz, -60° C., δ (ppm)=8.57(C-MeOCH₂ CH₂ ; 59.24 (H₃ COCH₂); 73.54 (MeOCH₂ CH₂); 110.41 (C-9, 10,19, 20); 123.37 (C-3, 6, 13, 16); 133.54 (C-4, 5, 4, 15); 140.28, 142.80(C-1, 2, 7, 8, 11, 12, 17, 18).

Mass spectrum of (9) EI, 75 eV: m/z=542 (M+, 81%); 497 (M--MeOCH₂ +,100%); 452 (M--2MeOCH₂ +, 20%); 407 (M--3MeOCH₂ +, 24%); 375 (M--3MeOCH₂--MeOH+, 3%).

IR spectrum; CsI pellet, ν (cm⁻¹) 2920, 2867 (CH), 1113 (C-0, ether) ,1459, 1017, 816.

UV/VIS spectrum of (9) CH₂ Cl₂, λmax[nm] (ε)=370 (1.4×10⁵); 563(3.5×10⁴); 602 (3.3×10⁴); 634 (4.7×10⁴).

¹ H-NMR spectrum of 2-methyl-7,12,17-tri(methoxyethyl)porphycene, CDCl₃,80 MHz, δ (ppm)=3.12 (wide singlet) NH; 3.6 (singlet, 12H) H₃ COCH₂ andH₃ C at C-2); 4.36 (singlet, 12H) MeOCH₂ CH₂ ; 9.25 (singlet, 1H), 9.34(3 singlets, 3H) H at C-3, 6, 13, 16; 9.68, 9.71 (2 singlets, 4H) H atC-9, 10, 19, 20.

Mass spectrum of 2-methyl-7,12,17-tri(methoxyethyl)porphycene, EI, 75eV: m/z=498 (M+, 78%); 453 (M--MeOCH₂ +, 100%); 408 (M--2MeOCH₂ +, 26%).

9-Acetoxy-2,7,12,17-tetrakis (methoxyethyl)porphycene

A solution of 542 mg (1 mmol) 2,7,12,17-tetrakis(methoxyethyl)porphycenein 75 ml CH₂ CL₂ freshly distilled over LiAlH₄, and 75 ml glacial aceticacid was combined with 179 mg (0.75 mmol) PbO₂ and stirred for 20 min.at room temperature. The reaction mixture was then poured into 500 mlwater and extracted with 250 ml dichloromethane. After washing theorganic phase once with concentrated aqueous sodium hydrogen carbonate(150 ml) and twice with water (200 ml), the organic layer was evaporatedunder vacuum. The residue was chromatographed withdichloromethane/ethylacetate (1:1) on silica gel (column 40×5 cm). Thefirst eluted compound consisted of unchangedtetrakis(methoxyethyl)-porphycene (195 mg). Following evaporation of thesolvent and crystallization the second, largest fraction frommethanol/water, the title compound9-acetoxy-tetrakis(methoxyethyl)porphycene was obtained in the form ofsmall, violet needles having a melting point of 107° C. Yield: 153 mg,40%

Mass spectrum, EI, 70 eV, m/z=600 (M⁺, 87%); 558 ([M--CH₂ CO]⁺, 100%);557 ([M--CH₃ CO]+, 22%); 513 ([M--MeOCH₂ --CH₂ CO]+, 36%).

UV/VIS spectrum, CH₂ Cl₂, λmax[nm] (ε)=370 (1.39×10⁵); 382 (9.1×10⁴);562 (2.9×10⁴); 604 (3.2×10⁴); 633 (3.2×10⁴); 640 (3.0×10⁴).

IR spectrum, CsI pellet, ν (cm⁻¹) 2924, 2872 (C--H), 1758 (C═O), 1115(C--O), 1458, 1074, 1002, 816.

Solubility of the title compound in selected solvents: Excellent: ethylacetate, THF, CHCl₃, CH₂ Cl₂ ; Good: DMSO, DEET, DMF, Toluene, acetone;Moderate: EtOH, MeOH, i-propanol; Insoluble: hexane, water.

2,7-Bis(methoxyethyl)-12,17-di-n-propylporphycene

A stirred suspension under protective gas of 17.4 g (260 mmol) zincpowder and 1.7 g (16.8 mmol) anhydrous CuCl in 700 ml of THF freshlydistilled over LiAlH₄ was mixed in 30 minutes dropwise with 14.2 ml (130mmol) TiCl₄. Subsequently the mixture was heated under reflux for threehours. At this stage, a solution of 1.36 g (5 mmol)5,5'-diformyl-4,4'-di-n-propyl-2,2'-bipyrrole and 1.52 g (5 mmol)5,5'-diformyl-4,4'-bis(methoxyethyl)-2,2'-bipyrrole in 300 ml THF, wasadded, with stirring, within 45 minutes to the black McMurry reagent.The reaction was stirred for two minutes at the boiling temperature ofthe tetrahydrofuran and then cooled to 0° C. A this temperature 250 mlof 10% NH₃ solution were added dropwise over one hour. The reactionmixture was treated with 500 ml THF, stirred under oxygen for 90 minutesand filtered off. The residue was extracted with 200 ml of CH₂ Cl₂ andthe combined organic layers were evaporated under vacuum. The residue,which contained black polymers, was dissolved as thoroughly as possiblein dichloromethane and filtered over Celite. The black residue wasground up and extracted with further dichloromethane. The combinedorganic phases were evaporated under vacuum and the dark blue residuewas taken up into CH₂ Cl₂ and placed on an alumina column. (Brockmann,II--III activity, column 10×5 cm). All the blue, red fluorescingfractions were collected and rechromatographed with CH₂ Cl₂ /ethylacetate (100:4) on silica gel (column 25×5 cm). The first elutedcompound consisted of tetra-n-propylporphycene, followed by the maincompound bis(methoxyethyl)-di-n-propylporphycene. The third fraction wasthe tetrakis(methoxyethyl)porphycene, eluted with ethyl acetate. Afterdividing those three fractions, it was necessary to further remove smallquantities of minor compounds by recrystallization. The first fractionwith tetra-n-propylporphycene was recrystallized after evaporation ofthe solvent from dichloromethane/hexane.

By evaporation of the solvent and recrystallization of the secondfraction from CH₂ Cl₂ /MeOH, the title compoundbis(methoxyethyl)-di-n-propylporphycene was obtained in the form oflong, violet, metallically glistening needles having a melting point of142° C. The porphycene-tetraether (third fraction) was purified byrecrystallization from CH₂ Cl₂ /MeOH.

    ______________________________________                                        Total yield of three porphycenes:                                                                 22% (560 mg; 1.10 mmol)                                   2,7-bis(methoxyethyl)-12,17-di-n-                                             propylporphycene:   11% (280 mg; 0.55 mmol)                                   2,7,12,17-tetrakis(methoxyethyl)-                                             porphycene:         5.5% (146 mg; 0.27 mmol)                                  2,7,12,17-tetra-n-propylporphycene:                                                               5.5% (134 mg; 0.28 mmol)                                  ______________________________________                                    

¹ H-NMR spectrum of bis(methoxyethyl)-di-n-propylporphycene, CDCl₃, 300MHz, δ (ppm)=1.34 (triplet, 6H) --CH₂ CH₂ CH₃ ; 2.41 (multiplet, 4H)--CH₂ CH₂ CH₃ ; 3.14 (wide singlet, 2H) NH; 3.59 (singlet, 6H) --CH₂ CH₂OCH₃ ; 4.00 (triplet, 4H) --CH₂ CH₂ CH₃ ; 4.31 (singlet, 8H) --CH₂ CH₂OCH₃ ; 9.27 (singlet, 2H) H-13, H-16; 9.34 (singlet, 2H) H-3, H-6; 9.71(singlet, 4H) H-9, H-10, H-19, H-20.

¹³ C-NMR spectrum, CDCl₃, 75.5 MHz, δ (ppm)=14.51 (--CH₂ CH₂ CH₃); 25.22(--CH₂ CH₂ CH₃); 28.89 (--CH₂ CH₂ OCH₃); 30.45 (--CH₂ CH₂ CH₃); 58.99(--CH₂ CH₂ OCH₃); 74.09 (--CH₂ CH₂ OCH₃); 110.52 (C-9, C-10, C-19,C-20); 122.88 (C-13, C-16); 123.42 (C-6); 134.16 (C-4, C-5); 134.22(C-14, C-15); 140.65 (C-2, C-7); 143.34 (C-11, C-18); 143.82 (C-1, C-8);145.01 (C-12, C-17).

Mass spectrum, EI, 70 eV, m/z=510 (M⁺, 100%); 481 ([M--C₂ H₅.]⁺, 13%);466 ([M--C₃ H₈.]⁺, 31%); 466 ([M--MeOCH₂.]⁺, 88%); 420([M--2MeOCH₂.]⁺,32%); 255 (M²⁺, 4%).

UV/VIS spectrum, CH₂ Cl₂, δ max[nm] (ε)=370 (142000); 382 (100000); 562(36000); 601 (34000); 633 (49000).

IR spectrum, CsI pellet, ν (cm⁻¹) 2955, 2927, 2868 (C--H); 1116 (C--O);1458, 1214 , 1083, 1018, 816.

2,7,12,17-Tetrakis(methoxyethyl)porphycenatonickel (II)

A suspension of 380 mg (0.7 mmol) tetrakis(methoxyethyl)porphycene in120 mL of acetic acid was heated with reflux with 1.7 g (7 mmol)Ni(OAc)₂ -4H₂ O for five hours. The reaction can be followed by means ofthin layer chromatography (CH₂ Cl₂ /ethyl acetate (4:1), silica gel). Inso doing, the nickel complex appears as a less mobile, blue fractionwithout fluorescence. Following complete complexing, the mixture waspoured into 600 mL of water and extracted three times with 150 mL CHCl₃.The combined organic phases were washed twice with water and a saturatedNaHCO₃ solution and again twice with water, then dried over MgSO₄ andthe solvent evaporated under vacuum. 398 mg (0.67 mmol) bluish-violet,matted needles of the title compound having a melting point of 182° C.was obtained from the residue through recrystallization from CH₂ Cl₂/MeOH. The yield was 95%.

If the raw product of (9) obtained following the first chromatography isadded, a mixture of partially degraded porphycenes can be separated inthe form of its nickel complex even at this stage by means ofchromatography on silica gel (column 4×40 cm) with CH₂ Cl₂ /ethylacetate (3:1).

1H-NMR spectrum of the title compound, CDCl₃, 300 MHz, δ (ppm)=3.58singlet, 12H) H3COCH₂ ; 4.20 (A₂ B₂ system, 16H) MeOCH₂ CH₂ ; 8.82(singlet, 4H) H at C-3, 6, 13, 16; 9.28 (singlet, 4H) H at C-9, 10, 19,20.

Mass spectrum, DEI, 75 eV; m/z=599 (M+, 15%); 554 (M--MeOCH₂ +, 8%).

IR spectrum, CsI pellet, ν (cm⁻¹) 2887, 2870, 2810 (CH), 1117 (C-0,ether), 1489, 974, 839, 812.

UV/VIS spectrum CH₂ Cl₂, λmax[nm] (ε)=265 (3.1×10⁴); 387 (1.27×10⁵); 603(6.3×10⁴).

Bis-,tris-, and tetrakis(bromoethyl)porphycenes

120 mg (0.2 mmol) tetrakis(methoxyethyl)porphycenatonickel (II) weredissolved under protective gas in 150 mL of CH₂ Cl₂ freshly distilledover LiAlH₄ and treated with 100 mg (1.6 mmol) boric acid. The reactionwas cooled to -78° C. and 100 mg (75 μL, 0.8 mmol) BBr₃ were added atone time under cooling and in the dark. Cooling the boron tribromide to-20° C. facilitates its handling. The reaction was thawed over ten hoursand then 100 mL of 5% NaHCO₃ solution were added at 0° C. within 30minutes while stirring vigorously. Another 200 mL of CH₂ Cl₂ are addedand the organic phase was separated out. This was washed twice, eachtime with a saturated NaHCO₃ solution and water and dried over MgSO₄.The solvent was evaporated under vacuum and the residue was dried at 0.1torr.

The blue solid obtained was treated with 20 mL of 98% H₂ SO₄ and stirredfor 30 minutes. The resulting blue, red fluorescing solution was pouredinto 1.2 L of deionized water and extracted four times with 150 mL ofCHCl₃. The combined organic phases were washed with water and a 5%sodium hydrogen carbonate solution and the solvent was removed undervacuum. The residue was chromatographed twice with chloroform on silicagel (column 2×30 cm). From the first blue fraction of the secondchromatography, 29 mg (0.04 mmol) of 2,7,12,17tetrakis(bromoethyl)porphycene were obtained by means of crystallizationfrom CHCl₃ in the form of small, violet needles, which did not exhibit amelting point until 300° C. The yield was 20%.

A similar procedure can be applied to the three isomericbis(bromoethyl)bis(methoxyethyl)porphycenes and2,7,12-tris(bromoethyl)-17-(methoxyethyl)porphycene. In the case ofbis(bromoethyl)bis(methoxyethyl)porphycenes, 30 mg (0.48 mmol) boricacid and 60 mg (0.24 mmol) BBr₃ were used for 120 mg (0.2 mmol) of thenickel complex. To isolate the tris(bromoethyl) compound, 50 mg (0.8mmol) B(OH)₃ and 100 mg (0.4 mmol) BBr₃ were added to the same quantityof the nickel complex. The yield was 25% and 30%, respectively. The tris(bromoethyl) porphycene begins to decompose at 250° C., becoming black,without exhibiting a melting point until 300° C. when heated rapidly.

Mass spectrum of 2,7,12,17-tetrakis(bromoethyl)porphycenatonickel (II),EI, 75 eV: m/z=794/96 (M+, 3%); 704/06 (M-Br+, 58%); 467/69 (M-4Br+,30%).

¹ H-NMR spectrum of 2,7,12,17tetrakis(bromoethyl) porphycene (TBEP), D₂SO₄, 80 MHz, δ (ppm)=4.32 and 4.53 (2 triplets, 16H) BrCH₂ CH₂ ; 10.16(singlet, 4H) H at 9, 10, 19, 20.

IR spectrum of (TBEP), CsI pellet, ν (cm⁻¹)=2958, 2920 (CH), 1261, 1046,799.

UV/VIS spectrum of (TBEP), CH₂ Cl₂, λmax[nm] (ε)=369 (1.02×10⁵); 383(7.9×10⁴); 564 (2.5×10⁴); 605 (2.9×10⁴); 637 (3.2×10⁴.)

¹ H-NMR spectrum of bis(bromoethyl)bis(methoxyethyl)porphycene (mixtureof isomers), CDCl₃, 80 MHz, δ (ppm)=3.20 (wide singlet) NH; 3.61(singlet, 6H) H₃ COCH₂ ; 4.33 (singlet, 8H) MeOCH₂ CH₂ ; 4.26, 4.50,4.59 (3 multiplets, 8H) BrCH₂ CH₂ ; 9.37 (multiplet, 4H) H at C-3, 6,13, 16; 9.76, 9.66 (3 multiplets, 4H) H at C-9, 10, 19, 20.

¹ H-NMR spectrum of 2,7,12-tris(bromoethyl)-17-methoxyethylporphycene,CDCl₃, 80 MHz, δ (ppm)=3.11 (wide singlet) NH; 3.61 (singlet, 3H) H₃COCH₂ ; 4.19, 4.58 (2 multiplets, 12H) BrCH₂ CH₂ ; 4.32 (singlet, 4H)MeOCH₂ CH₂ ; 9.34, 9.35 (2 singlets, 4H) H at C-3, 6, 13, 16; 9.62,9.67, 9.68 (3 singlets, 4H) H at C-9, 10, 19, 20.

Mass spectrum, EI, 75 eV; m/z=497 (M-2Br--MeOH+, 2%); 94/96 (CH₃ Br+,100%).

IR spectrum, CsI pellet, ν (cm⁻¹) 2962, 2925 (CH), 1140 (C-0, ether),963, 816.

2,7,12,17-Tetravinylporphycene

At room temperature while stirring in the dark, 243 mg (248 μL, 1.6mmol) DBU were added all at once to a solution of 14.8 mg (20 μmol)tetrakis(bromoethyl)porphycene in 50 mL of absolute THF. After thirtyminutes, the agitator was turned off and the mixture left to stand atroom temperature for two days. Subsequently the greenish-blue solutionwas treated with 80 mL of CH₂ Cl₂ and poured into 80 mL of 0.5% HCl. Theorganic phase was shaken out and washed with water and a 2% NaHCO₃solution, dried over Na₂ SO₄ and the solvent was evaporated undervacuum. The residue was chromatographed with CH₂ Cl₂ on aluminum oxide(Brockmann, II-III activity stage, column 2×10 cm) and the first greenfraction was collected. The solvent was slowly evaporated under a slightvacuum and the remaining fine crystalline solid was washed with 3 mL ofice cooled, absolute pentane. Following drying under a high vacuum, 4.1mg (10 μmol) tetravinylporphycene were obtained. The title compounddecomposed even with traces of oxygen in the presence of light. Theyield was 50%.

All reagents and solvents were purged of oxygen by introducing inert gasand all purification steps were carried out under subdued light, as wasthe reaction.

¹ H-NMR spectrum of, CD₂ Cl₂, 300 MHz, δ (ppm)=3.64 (wide singlet) NH;6.01 (doublet of doublets, 4H) CH═CH₂ -cis³ Jcis═11.0 Hz; 6.68 (doubletof doublets, 4H) CH═CH₂ -trans³ Jcis═17.4 Hz; 8.31 (doublet of doublets,4H) CH═CH₂ ; 9.68 (singlet, 4H) H at C-3, 6, 13, 16; 9.86 (singlet, 4H)H at C-9, 10, 19, 20.

UV/VIS spectrum, CH₂ Cl₂, λmax[nm] (ε)=383 (3.2×10⁴); 597 (1.1×10⁴); 642(1.5×10⁴); 676 (1.3×10⁴).

2-Bromoethyl-7,12,17-tris(methoxyethyl)porphyceneatonickel (II)

A solution of 419 mg (0.7 mmol) tetrakis(methoxyethyl)porphycenatonickelcomplex in 250 mL of CH₂ Cl₂ freshly distilled over LiAiH₄ was treatedwith 62 mg (1 mmol) boric acid and 126 mg (48 μL, 0.5 mmol) BBr₃ wereadded all at once under protective gas at -78° C. The mixture was leftto thaw over eight hours and 50 mL of 5% NaHCO₃ solution were addeddropwise over 10 minutes at 0° C. The organic phase was separated offand washed sequentially with a saturated NaHCO₃ solution and water.Following drying over MgSO₄, the solvent was evaporated under vacuum andpurified by means of chromatography on silica gel (column 4×40 cm, CH₂Cl₂ /ethyl acetate/methanol (80:20:1)). The first three fractionscontained various ether-split nickel porphycenes; the2-bromoethyl-7,12,17-tris(methoxyethyl)porphycenato-nickel (II) waseluted as the fourth fraction. Following removal of the solvent andrecrystallization from CH₂ Cl₂ /methanol there resulted 159 mg (0.245mmol, yield 35%, reaction yield 70%) of bluish-violet crystals having amelting point of 186°-189° C. The fifth blue band yielded afterevaporation of the solvent and crystallization 209 mg (0.35 mmol) of theeduct, 2,7,12,17-tetrakis(methoxyethyl)porphycenato-nickel (II).

¹ H-NMR spectrum, CDCl₃, 300 MHz, δ (ppm)=3.58, 3.59 (2 singlets, 9H) H₃COCH₂ ; 4.06, 4.10 (2 multiplets, 16 H) MeOCH₂ CH₂ and BrCH₂ CH₂ ; 8.34,8.45 (2 singlets, 2H) H at C-3, 6; 8.55, 8.57 (2 singlets, 2H) H atC-13, 16; 8.70 (A₂ B₂ system, 2H) H at C-19, 20; 8.95 (singlet, 2H) H atC-9, 10.

¹³ C-NMR spectrum, CDCl₃, 75.5 MHz, δ (ppm)=29.1 (CH₂ CH₂ OMe; 32.3,32.4 (CH₂ CH₂ Br); 59.0 (CH₂ OCH₃); 73.7 (CH₂ CH₂ OMe); 106.6, 106.8,107.0, 107.2, (C-9, 10, 19, 20); 119.1, 119.4, 119.5, 119.6 (C-3, 6, 13,16); 145.1, 144.1, 143.8, 142.6, 146.6 (C-4, 5, 14, 15, 1, 2, 7, 8, 11,12, 17, 18).

IR spectrum, CsI pellet, ν (cm⁻¹)=2920, 2870 (CH) 1116 (C-0, ether),1618, 1560, 1488, 974, 811.

Mass spectrum, EI, 75 eV: m/z=648 (M+, 45%); 603 (M--MeOCH₂ +, 54%); 432(M-3MeOCH₂ --Br+, 18%); 418 (M-3MeOCH₂ -CH₂ Br+, 21%); 94 (CH₃ Br+,35%); 80 (HBr+, 100%).

UV/VIS spectrum, CH₂ Cl₂, λmax[nm] (ε)=264 (3.2×10⁴); 387 (1.28×10⁵);605 (6.5×10⁴).

2-Bromoethyl-7,12,17-tris(methoxyethyl)porphycene

To demetallate, 97.2 mg (0.15 mmol) of the above-describedbromoethylporphycenatonickel complex were suspended in 12 mL ofconcentrated sulfuric acid and stirred for ten minutes until a clearsolution was produced. The reaction solution was poured in 1 L of waterand extracted three times with 150 mL of CHCl₃. The combined organicphases were washed three times with water and once with a 1% NaHCO₃solution and dried over MgSO₄. Following evaporation of the solventunder vacuum and recrystallization from CH₂ Cl₂ /MeOH, 80 mg (0.135mmol) of the title compound were obtained in the form of long, violet,metallically glistening needles with a melting point of 164° C. Yield:90 percent.

Elementary analysis: calc. C 62.94% H 5.96% N 9.47% Br 13.51% found C62.87% H 5.87% N 9.55% Br 13.56%

¹ H-NMR spectrum, CF₃ CO₂ D, 300 MHz, δ (ppm)=3.83, 3.84 (2 singlets,9H) H₃ COCH₂ ; 4.27 (triplet, 2 H) BrCH₂ CH₂ ; 4.56, 4.66 (2 multiplets,14H) MeOCH₂ CH₂ and BrCH₂ CH₂ ; 10.03 (multiplet 4H) H at C-3, 6, 13,16; 10.54 (multiplet, 4H) H at C-9, 10, 19, 20.

¹³ C-NMR spectrum, CDCl₃, 75.5 MHz, δ (ppm)=28.85 (MeOCH₂ CH₂); 32.2,32.9 (BrCH₂ CH₂); 59.0 (H₃ COCH₃); 73.9 (MeOCH₂ CH₂); 110.5, 110.8,110.9, 111.1, (C-9, 10, 19, 20); 123.5, 123.6, 123.9, 124.0 (C-3, 6, 13,16); 133.5, 134.1, 134.2, 135.0 (C-4, 5, 14, 15); 140.58, 140.61, 140.9,141.0, 142.9, 143.0, 144.5, (C-1, 2, 7, 8, 11, 12, 17, 18).

IR spectrum, CsI pellet, ν (cm⁻¹)=2908, 2860 (CH) 1116 (C-0, ether) ,1558, 1208, 937, 814.

Mass spectrum, EI, 75 eV: m/z=592 (M+, 8%); 547 (M--MeOCH₂ +, 2%); 511(M--Br+, 1%).

UV/VIS spectrum, CH₂ Cl₂, λmax[nm] (ε)=243 (1.3×10⁴); 370 (1.33×10⁵);832 (9.5×10⁴); 564 (3.4×10⁴); 546 (3.4×10⁴); 603 (3.2×10⁴); 635(4.5×10⁴).

2-Vinyl-7,12,17-tris(methoxyethyl)porphycene

All of the reagents and solvents used in the following procedure werepurged of oxygen by introducing inert gas and all of the purificationsteps were carried out, as in the reaction itself, under subdued light.

71 mg (0.12 mmol) of 2-bromoethyl-7,12,17tris(methoxyethyl)porphycenewere dissolved in 50 mL of absolute THF and treated with 1.8 g (1.86 ml,12 mmol) DBU under protective gas. The reaction solution was stirred at40° C. for 90 minutes in the dark and subsequently treated with 150 mLof absolute dichloromethane. The mixture was poured into 100 mL of 5%hydrochloric acid, neutralized by shaking with a 2% NaHCO.sub. 3solution and then washed with water. The organic phase obtained wasseparated off and evaporated under a slight vacuum. The residue waschromatographed with CH₂ Cl₂ on aluminum oxide (Brockmann, activitystage II-III, column 3×10 cm). Following crystallization fromdichloro-methane and drying under oil pump vacuum, 52.6 mg (0.103 mmol)of the title compound were obtained from the single mobile blue fractionas needle-shaped crystals having a melting point of 119°-120° C. (withdecomposition). Yield: 86%.

¹ H-NMR spectrum, CDCL₃, 300 MHz, δ (ppm)=3.05 (wide singlet) NH; 3.59,3.95, 3.40 (3 singlets, 9H) H₃ COCH₂ ; 4.28 (multiplet, 12H) MeOCH₂ CH₂; 5.95 (doublet of doublets, 1H) CH═CH₂ cis; 6.60 (doublet of doublets,1H) CH═CH₂ trans; 8.25 (doublet of doublets) CH═CH₂ ; 9.25, 9.26 (2singlets, 3H) H at C-3, 6, 13, 16; 9.53 (singlet, 1H) H at C-3; 9.60 (ABsystem, 2H) H at C-9, 10; 9.69 (AB system, 2H) H at C-19, 20.

Mass spectrum, FAb, 75 eV; m/z=510 (M+, 100%); 465 (M--MeOCH₂ +, 23 %).

IR spectrum, CsI pellet: ν (cm⁻¹) 2968, 2922, 2870 (CH), 1116 (C-0,ether) , 1727, 1557, 1460, 1440, 801.

UV/VIS spectrum, CH₂ Cl₂, λmax[nm] (ε)=373 (9.8×10⁴); 572 (2.6×10⁴); 613(2.8×10⁴); 643 (3.3×10⁴).

Cleavage of 2,7,12,17-tetrakis(methoxyethyl)porphycene with BBr₃

The following procedure was carried out in a totally dry and oxygen freeatmosphere with especially dried equipment and solvents.

70 μL (0.74 mmol) freshly distilled boron tribromide in 70 mL ofdichloromethane were added during 60 minutes to a vigorously stirredsolution of 542 mg (1 mmol) tetrakis(methoxyethyl)porphycene in 150 mLof the same solvent at -30° C. Over the next 16 hours, the mixture wasallowed to reach room temperature and 25 mL of a 8% aqueous solution ofsodium hydrogen carbonate were added in one portion. The precipitate wasfiltrated off by the aid of Celite®, washed with sodium hydrogencarbonate solution and with water. The collected solids were extractedwith methanol. The dichloromethane phase of the filtrate was extractedonce with sodium hyarogen carbonate solution, twice with water and thencombined with the methanol extract. The raw product mixture waspreadsorbed by evaporating the organic phase on addition of 15 g ofalumina, and fractionated on a column of silica gel (2×60 cm) withdichloromethane/ethyl acetate/ethanol (100:10:1). After a forerun of300-360 mg (50-65% depending on the extent of remaining water in solventand equipment) unchanged starting material(tetrakis(methoxyethyl)porphycene), the2-hydroxyethyl-7,12,17-tris(methoxyethyl)porphycene was eluted, whichwas then crystallized from toluene/hexane (1:1) to afford 17-18% (93 mg)of dark violet cubes melting at 131° C. By the use ofchloroform/methanol (8:1) the isomericbis(hydroxyethyl)bis(methoxyethyl)porphycenes as well as thetris(hydroxyethyl)mono(methoxyethyl)porphycene were eluted, which couldbe obtained in 10-12% (53 mg) and 4% (20 mg) yield, respectively.

2-Hydroxyethl-7,12,17-tris(methoxyethyl)porphycene

Mass spectrum: (75 eV)m/z=528 (80%; M⁺.); 497(10%; [M--HOCH₂.sup.. ]⁺);483 (100%; [M--CH₃ OCH₂.sup.. ]⁺).

IR spectrum: (CsI): ν (cm⁻¹) 3462 (OH); 2921; 2869; 1561; 1460; 1405;1215; 1115 (ether); 1017; 968; 884; 815.

UV/VIS spectrum: (dichloromethane) λ_(max) [nm] (ε)=370 (134000); 563(33600); 602 (31200); 635 (43900).

2,12-Bis(hydroxyethyl)-7,17-bis(methoxyethyl)porphycene (3rd fraction)

Mass spectrum: (75 eV) m/z=514 (90%; M⁺); 483 (40%; [M--HOCH₂.sup.. ]⁺);469 (100%; [M--CH₃ OCH₂.sup.. ]⁺).

¹ H-NMR spectrum: (80 MHz, DMSO-d6) δ (ppm)=9.92 (singlet 4 H) H-9,H-10, H-19, H-20; 9.67 (singlet 4 H) H-3, H-6, H-13, H-16; 5.12 (triplet2H)--OH; 4.31 (multiplet 8 H) HOCH₂ CH₂ ; 4.30 (singlet 8 H) H3COCH₂ CH₂; 3.50 (singlet 6 H) H₃ CO--; 3.09 (wide singlet 2 H) NH.

IR spectrum: (CsI) ν (cm⁻¹)=3424 (OH); 2912 (CH); 1870; 1560; 1459;1415; 1388; 1216; 1108; 1064; 1013; 974; 889; 815; 625; 522.

UV/VIS spectrum: (DMSO) λ_(max) [nm]=251 (10000); 309 (12300); 371(130000); 383 (92800); 530 (5600) (sh); 554 (22600) (sh); 562 (31900);601 (32100); 632 (44400).

2,7-Bis(hydroxyethyl-12,17-bis(methoxyethyl)porphycene and2,17-Bis(hydroxyethyl-7,12-bis(methoxyethyl)porphycene (4th fraction)

Mass spectrum: (75 eV) m/z=514 (100%; M⁺), 483 (40%; [M--HOCH₂.sup..]⁺); 469 (100%; [M--CH₃ OCH₂.sup.. ]⁺).

¹ H-NMR spectrum: (80 MHz, DMSO-d6) δ (ppm)=9.94 (singlet; 4 H) H-9,H-10, H-19, H-20; 9.68 (singlet; 4 H) H-3, H-6, H-13, H-16; 5.73(triplet; 2 H) --OH; 4.32 (multiplet; 8 H) HOCH₂ CH₂ ; 4.31 (singlet; 8H) H₃ COCH₂ CH₂ ; 3.50 (singlet; 6 H) --OCH₃ ; 3.09 (wide singlet; 2H)NH.

IR spectrum: (CsI) ν (cm⁻¹)=2877 (CH); 1851; 1654; 1560; 1459; 1380;1215; 1116; 1050; 1007; 887; 815; 626, 522.

UV/VIS spectrum: (DMSO) λ_(max) [nm] (ε)=262 (8000); 310 (13000); 370(136700); 383 (99000); 529 (5800) (sh); 551 (20800) (sh); 562 (34200);601 (34600); 632 (48000).

2,7,12-Tris(hydroxyethyl)-17-methoxyethylporphycene

Mass spectrum: (75 eV) m/z=500 (100%; M⁺.); 469 (70%; [M--HOCH₂.]⁺); 455(75%; [M--CH₃ OCH₂.]⁺).

IR spectrum: (CsI) ν (cm⁻¹)=3331 (OH); 2870 (CH); 1870; 1460; 1371;1220; 1046; 1008; 967; 886; 816; 626; 518.

UV/VIS spectrum: (DMSO) λ_(max) [nm] (ε)=370 (134000); 382 (97000); 563(33600); 602 (31200); 635 (43900).

2,7,12,17-Tetrakis(acetoxyethyl)porphycene

At -30° C. and in an atmosphere of argon a solution of 108.4 mg (0.2mmol ) tetrakis (methoxyethyl) porphycene in 100 ml freshly drieddichloromethane was treated with 0.2 ml (2.1 mmol) pure borontribromide. The solution was stirred for 16 hours, quenched with 10 mlof dilute ammonia and the precipitate was separated, washed withdichloromethane, water and ether and dried in vacuo. The crude2,7,12,17-tetrakis(hydroxyethyl)porphycene was dissolved in 25 mlpyridine and 5 ml acetic anhydride stirred for 16 hours, evaporated andwashed with water. The residue was chromatographed withdichloromethane/acetone (40:1) on silica gel (2×15 cm). The second bluefraction contained 66 mg (50%) of the title compound, which afterrecrystallization from benzene yielded violet needles melting at188°-189° C.

Mass spectrum: (75 eV) m/z=654 (100%; M⁺.); 594 (35%; [M--CH₃ CO₂ H]⁺.);581 (15%; [M--CH₃ CO₂ CH₂.sup.. ]⁺); 534 (35%; [M--2CH₃ CO₂ H]⁺.).

1H-NMR spectrum: (80 MHz, CDCl₃) δ (ppm)=9.67 (singlet; 4 H) H-9, H-10,H-19, H-20; 9.29 (singlet; 4H) H-3, H-6, H-13, H-16; 4.99 (AX-System ³J(H-3a, H-3b)=7.0 Hz; 8 H) H-2a, H-7a, H-12a, H-17a; 4.34 (AX-System;8H) H-2b, H-7b, H-12b, H-17b; 3.06 (wide singlet; 2H) NH; 2.14 (singlet,12 H)--OAc.

IR spectrum: (CsI) ν (cm⁻¹)=2955 (CH); 1733 (C═O); 1465; 1373; 1238;1027 (C--O--ester); 965; 887; 806; 608; 517; 478.

US/VIS spectrum: (dichloromethane) λ_(max) [nm] (ε)=242 (14000); 369(144000); 381 (103000); 564 (37000); 603 (35000); 635 (50000).

2,7,12,17-Tetrakis(hydroxyethyl)porphycene

32.7 mg (50 μmol) Tetrakis(acetoxyethyl)porphycene were dissolved in 20ml of dry tetrahydrofuran and 27 mg (0.5 mmol) sodium methoxide in 1 mlabsolute methanol was added. The solution was allowed to stand withoutagitation while the pure tetrakis(hydroxyethyl)porphycene crystallizedas small violet needles, which did not melt below 350° C. (yield: 22mg=90%).

Mass spectrum: (75 eV) m/z=486 (50%; M⁺.); 455 (80%; [M--HOCH₂.]⁺); 425(30%; [M--HOCH₂.--OCH₂ ]⁺); 393 (25%; [M--3HOCH₂.]⁺).

IR spectrum: (CsI) ν (cm⁻¹)=3328 (OH); 2895; 1463; 1372; 1220; 1043(C--O); 880; 824; 396.

UV/VIS spectrum: (DMSO) λ_(max) [nm] (ε)=372 (92400); 385 (83000); 570(26200); 611 (20400); 647 (28300).

2-Chloroethyl-7,12,17-tris(methoxyethylporphycene

39.6 mg (75 μmol) 2-Hydroxyethyl-7,12,17-tris(methoxyethyl)porphycenewere dissolved in 10 ml dimethylformamide (free from water and amine)and at 0° C. 2 ml (27.5 mmol) of purified thionylchloride were addedquickly. The solution warmed up and was directly poured into 100 mldilute aqueous ammonia. The ammonia was extracted three times withtrichloromethane, and the combined organic phases were then washed fivetimes with water. After evaporation of the solvents the crude productwas chromatographed on silica gel (2×80 cm) with trichloromethane/ethylacetate (20:1; third blue fraction) and repeatedly recrystallized fromdichloromethane/hexane and washed with ether and hexane. This proceduregave 4.1 mg (10%) chloroethylporphycene as tiny violet needles.

Mass spectrum: (70 eV) m/z=546/548 (45%; M⁺.); 512 (90%; [M+H.--Cl.]⁺.);501/503 (55%; [M--CH₃ OCH₂.]⁺ ; 482 (15%; [M--CH₃ O.--Cl.]⁺.); 467(100%; [M+H--CH₃ OCH₂.--Cl.]⁺).

¹ H-NMR spectrum: (80 MHz, CDCl₃) δ (ppm)=9.69 (singlet; 2 H) H-9, H-10;9.63 (A₂ B₂ -System; 2 H) H-19, H-20; 9.30 (singlet; 4 H) H-3, H-6,H-13, H-16; 4.42 (A₂ B₂ -System; 4 H) H-2a, H-2b; 4.30 (singlet; 12 H)H-7a, H-7b, H-12a, H-12b, H-17a, H-17b; 3.60 (singlet; 12H)--OCH₃ ; 3.04(broad singlet; 2 H)--NH.

IR spectrum: (CsI) ν (cm⁻¹)=2984 (CH); 2903 (CH); 2808 (CH); 1121 (CO);1846; 1560; 1458; 1420; 1391; 1263; 1214; 1066; 1019; 999; 969; 885;819; 768; 692; 652; 553; 520; 497.

Methanesulfonate of 2-hydroxyethyl-7,12,17-tris(methoxyethyl)porphycene

To a well-stirred solution of 52.8 mg (0.1 mmol)2-hydroxyethyl-7,12,17-tris(methoxyethyl)porphycene in 100 mldichloromethane and 9 ml pyridine were added during one hour 8.1 ml(1.05 mmol) methanesulfonylchloride. After another hour the solution waspoured onto 200 ml ice chilled water, the organic phase was separatedand the aqueous phase was extracted twice with dichloromethane. Thecombined organic phases were washed five times with water, the solventswere evaporated and the resulting blue oil was chromatographed thricewith trichloromethane/ethyl acetate (20:1) on silicagel (2×20cm). Thecontent of the blue fractions were recrystallized fromdichloromethane/petrol to yield 55 mg (91%) of violet at 145° C. meltingcrystals.

Mass spectrum: (75 eV)=m/z=606 (2%; M⁺.); 562 (2%; [M--CH₃ OCH₂.]⁺); 512(10%; [M--CH₂ SO₂ OCH₂.]⁺); 467 (13%; [M--CH₂ SO₂ O--CH₃ OCH₂.]⁺); 96(80%; CH₂ SO₂ O⁺.); 79 (100%; CH₃ SO₂ ⁺.).

IR spectrum: (CsI) ν (cm⁻¹)=2978 (CH); 2869 (CH); 1357 (S═O); 1176(S--O); 1114 (C--O); 1852; 1560; 1460; 1390; 1215; 1069; 1019; 973; 886;816; 728; 649; 626; 556; 528; 508.

UT/VIS spectrum: (dichloromethane) λ_(max) [nm] (ε)=242 (13400); 310(12300); 369 (141000); 381 (104000); 532 (6200); 563 (35700); 603(34100); 635 (48400).

2,3,4,6Tetra-O-acetyl-β-D-galactopyranoside of2-hydroxyethyl-7,12,17-tris(methoxyethyl)-porphycene

1 g of dry, freshly prepared silver carbonate and 1 g anhydrous sodiumsulfate were added to a solution of 42.2 mg (0.08 mmol)2-hydroxyethyl-7,12,17-tris(methoxyethyl)porphycene and 658 mg2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide in 50 ml ofanhydrous dichloromethane, and the mixture was stirred in the dark withrigorous protection from moisture until thin layer chromatography (tlc)(silica gel: dichloromethane/methanol, 20: 1) indicated thedisappearance of educt (about 3 days). The reaction mixture was filteredthrough a pad of Celite, and the inorganic solids were washed withdichloromethane.

The filtrate and washings were combined, washed with water, dried(sodium sulfate) and evaporated to give a syrup which was fractionatedby repeated recrystallization from ethanol and finally ether/pentane.This procedure yielded 6.9 mg 910%) of violet cubes melting at 95° C.

Mass spectrum: (75 eV) m/z=858 (100%; M+.); 814 (45%; [M--CH₂ CO]⁺.);511 (10%; [M--C₆ H₅ O(OAc)₄ O.]⁺); 497 (10%; [M--C₆ H₅ O(OAc)₄ OCH₂.]⁺);375 (5%; [M--C₆ H₅ O(OAc)₄ O--3CH₃ OCH₂.]⁺.); (80%; CH₃ CO⁺.).

IR spectrum: (CsI) ν (cm⁻¹)=2932 (CH); 1752; (C═O); 1560; 1460; 1371;1227; 1114; 1057; 966; 888; 814; 602; 536.

UV/VIS spectrum: (dichloromethane) λ_(max) [nm] (ε)=242 (13100); 309(12300); 369 (140000); 382 (100000); 532 (6000) (sh); 563 (35100); 602(33500); 634 (47500).

β-D-Galactopyranoside of2-hydroxyethyl-7,12,17-tris(methoxyethyl)porphycene

A solution of 17.2 mg (0.02 mmol) of the tetra-O-acetyl-compound (themother liquors of the previous reaction could also be used) in 10 mlabsolute tetrahydrofuran was treated with methanolic 0.05 M sodiummethoxide (40 ml). The solution was kept for 2 hours at roomtemperature, and 10 ml brine was added was well as 20 ml water. Theorganic phase was separated, the aqueous phase was extracted twice was20 ml tetrahydrofuran and the combined extracts were washed thrice withdilute aqueous sodium chloride, dried (sodium sulfate) and evaporated.The resulting residue was recrystallized from methanol to yield, afterwashing with water and cold ether small violet needles. m.p.=124° C.

IR spectrum: (CsI) ν (cm⁻¹)=3417 (OH); 2926 (CH); 1116 (C--O); 1561;1461; 1383; 1218; 1018; 966; 888; 816; 626; 529.

UV/VIS spectrum: (ethanol) λ_(max) [nm] (ε)=373 (125800); 384 (103900)(sh); 572 (33500); 613 (37400); 645 (44700).

2-Cyanoethyl-7,12,17-tris(methoxyethyl)porphycene

202 mg (0.33 mmol) methanesulfonate or 197 mg (0.33 mmol) monobromoethylporphycene were dissolved in 120 ml dry dimethylsulfoxide, and sodiumcyanide (491 mg/10 mmol, dried for 16 hours at 110° C.) was added. Thesuspension was stirred in the dark under an atmosphere of argon until nomore educt could be detected (tlc, silica gel: dichloromethane/acetone,40:1, 3 hours). The dimethylsulfoxide was distilled off at an maximumbath temperature of 50° C., and the residue was taken up in 300 mltrichloromethane and washed with three 100 ml portions of water. Afterdrying and evaporating the solvent the resulting product wasfractionated on a column (3×30 cm) of silica gel eluting withdichloromethane/ethyl acetate (15:1). When the bromo compound is used asthe starting material, protection from light is advisable.

The second blue fraction afforded after recrystallization from benzene135 mg (75%) in the case of the methanesulfonate as starting material,and 104 mg (58%) in the case of reacting with the bromide, of blueviolet needles of the nitrile; m.p. 166°-167° C.

Mass spectrum: (70 eV) m/z=537 (60%, M⁺.); 492 (100%, [M--CH₃ OH]⁺.);452 (4%, [M--CH₃ OCH₂.]⁺); 447 (10%, [M--2CH₃ OCH₂.]⁺); 407 (20%,[M--NCCH₂ --2CH₃ OCH₂.]⁺); 402 (15%, [M--3CH₃ OCH₂.]⁺); 362 (10%,[M--NCCH₂.--CH₃ OCH₂.]⁺).

IR spectrum: (CsI) ν (cm⁻¹)=2920; 2900 (CH); 2243 (CN); 1846; 1215; 1119(C--O).

UV/VIS spectrum: (dichloromethane) λ_(max) [nm] (ε)=370 (115000); 382(86700); 564 (29000); 603 (28700); 635 (40400).

2,7,12-Tris(methoxyethyl)-17-methoxypropionylporphycene

A suspension of 53.7 mg (0.1 mmol) cyanoethylporphycene in 15 mlanhydrous methanol was saturated at 0° C. with dry hydrogen chloride, sothat the porphycene was completely dissolved and then stirred for 18hours under protection from light. The now green solution was added to100 g ice, neutralized with aqueous 5N sodium hydroxide and theprecipitate was extracted with 200 ml dichloromethane. The solution waswashed with water, dried, the solvent was evaporated and the product waspurified by chromatography with 8:1 dichloromethane/acetone (1.5×10 cm)followed by recrystallization from benzene/hexane to afford 46.1 mg(81%) of violet needles, which melted at 137°-139° C.

Mass spectrum: (70 eV) m/z=570 (80%, M⁺); 525 (100%, [M--CH₃ OCH₂.]⁺);480 (20%, [M--2CH₃ OCH₂.]⁺.).

IR spectrum: (CsI) ν (cm⁻¹)=2870 (CH); 1849; 1736 (C═O); 1562; 1458;1389; 1361; 1213; 1116 (C--O--ester); 1067 (C--O--ether); 1018; 998;968; 882; 812; 710; 546; 364.

UV/VIS spectrum: (dichloromethane) λ_(max) [nm] (ε)=370 (146000); 382(105000); 563 (37200); 602 (35500); 634 (50700) .

2-carboxyethyl-7,12,17-tris(methoxyethyl)porphycene

A solution of 45.6 mg (80 μmol),2,7,12-tris(methoxyethyl)-17-methoxypropionylporphycene in 15 mltetrahydrofuran was treated with 10 ml aqueous potassium hydroxide (2N)and stirred for 40 hours in the dark. The precipitate was separated fromthe nearly colorless solution, washed successively with water anddichloromethane and taken up in a mixture of dichloromethane and 1Nhydrochloric acid. The dichloromethane phase was twice washed with 0.5Nhydrochloric acid, dried over magnesium sulfate, and evaporated to give29 mg (72%) of a microcrystalline powder.

Mass spectrum: (75 eV) m/z=556 (60%; M⁺.); 511 (100%, [M--CHO₂.]⁺ ;[M--CH₃ OCH₂.]⁺); 466 (25%, [M--2CH₃ OCH₂.]⁺ ; [M--CHO₂.--CH₃ OCH₂.]⁺);421 (25%, [M--CO2H.--2CH3OCH₂.]⁺); 407 (10%, [M--CH₂ CO₂ H.--2CH₃OCH₂.]⁺); 375 (10%, [M--CO2H._(--3CH3OCH2).]+.).

¹ H-NMR spectrum: (80 MHz, CF₃ COOD) δ (ppm)=10.61 (wide singlet, 4 H)C-9, C-10, C-19, C-20; 10.09 (multiplet, 4 H) C-3, C-13, C-16; 4.67(multiplet; 16 H) C-2a, C-2b, C-7a, C-7b, C-12a, C-12b, C-17a, C-17b;3.91 (singlet, 9H) --OCH.

IR spectrum: (CsI) ν (cm⁻¹)=3444 (OH); 2922 (C--H); 1710 (C═O); 1562;1459; 1208; 1117 (C--O); 1016; 964; 883; 812.

UV/VIS spectrum: (dichloromethane/4% trifluoroacetic acid) λ_(max) [nm](ε)=370 (120000); 382 (90000); 562 (30000); 602 (28000); 634 (41000).

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

What is claimed as new and desired to be secured by Letters Patent ofthe United States is:
 1. A porphycene having the structure ##STR4##wherein each R¹ is, independently, (a) --(CH₂)_(n) -X where X is anamino acid, oligopeptide covalently bonded by an ether-, ester- oramine-bond or where X is --Y--(CH₂)_(n) -porphycene², where porphycene²is a compound of the same said structure, n=1-4 and Y is a direct bond;--O--; or --CH═CH--; or(b) where one, two or three of the substituentsR¹ are C₁₋₆ alkyl or C₆₋₂₀ carbocyclic aryl and the remainingsubstituents are as above under (a) and pharmaceutically acceptablesalts and metal complexes thereof.
 2. A pharmaceutical compositioncomprising the porphycene of claim 1 and a pharmaceutically acceptablecarrier or diluent.
 3. The pharmaceutical composition of claim 2,wherein said composition is a solution of said porphycene in water,water-alcohol or dimethyl sulfoxide.
 4. A method of photodynamictherapy, comprising the steps of:administering to a mammal in needthereof, an effective amount or,the porphycene of claim 1, andirradiating said mammal with light at a wavelength in the absorptionspectrum of said porphycene.
 5. The method of claim 4, wherein saidadministering is topical administration.
 6. The method of claim 4,wherein said administering is enteral, parenteral or intramuscularadministration.
 7. A method of purifying or decontaminating a fluid,comprisingcontacting said fluid with the porphycene of claim 1, andirradiating said fluid in contact with the porphycene with light at awavelength in the absorption spectrum of said porphycene.
 8. The methodof claim 7, wherein said fluid is blood.
 9. The method of claim 7,wherein said porphycene is covalently bonded to a stationary supports.10. The compound 9-acetoxy-2,7,12,17-tetrakis(methoxyethyl)porphycene.11. A method of photodynamic therapy, comprising the stepsof:administering to a mammal in need thereof, an effective amount of theporphycene of claim 10, and irradiating said mammal with light at awavelength in the absorption spectrum of said porphycene.
 12. Theporphycene of claim 1, wherein X is a naturally occurring amino acid.13. The porphycene of claim 1, wherein X is an oligopeptide having 2-6amino acid residues.
 14. The porphycene of claim 13, wherein X is anoligopeptide having 2-3 amino acid residues.
 15. A porphycene having thestructure ##STR5## wherein each R¹ is, independently, (a) --(CH₂)_(n) -Xwhere X is an amino acid, oligopeptide covalently bonded by an ether-,ester- or amine-bond or where X is --Y--(CH₂)_(n) -porphycene², whereporphycene² is a compound of the same said structure, n=1-4 and Y is adirect bond; --O--; or --CH═CH--; or(b) wherein 1, 2, or 3 of thesubstituents R¹ are C₁₋₆ alkyl and the remaining substituents are asabove under (a).